@article{pmid31740615,

title = {Shining light on dark matter in the genome},

author = {Dongyin Guan and Mitchell A Lazar},

doi = {10.1073/pnas.1918894116},

issn = {1091-6490},

year  = {2019},

date = {2019-12-01},

journal = {Proc Natl Acad Sci U S A},

volume = {116},

number = {50},

pages = {24919--24921},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31527256,

title = {Identification of  as a human diabetes susceptibility gene with a role in β cell insulin secretion},

author = {Taiyi Kuo and Michael J Kraakman and Manashree Damle and Richard Gill and Mitchell A Lazar and Domenico Accili},

doi = {10.1073/pnas.1904311116},

issn = {1091-6490},

year  = {2019},

date = {2019-10-01},

journal = {Proc Natl Acad Sci U S A},

volume = {116},

number = {40},

pages = {20033--20042},

abstract = {Fine mapping and validation of genes causing β cell failure from susceptibility loci identified in type 2 diabetes genome-wide association studies (GWAS) poses a significant challenge. The  locus on chromosome 15 confers diabetes susceptibility in every ethnic group studied to date. However, the causative gene is unknown. FoxO1 is involved in the pathogenesis of β cell dysfunction, but its link to human diabetes GWAS has not been explored. Here we generated a genome-wide map of FoxO1 superenhancers in chemically identified β cells using 2-photon live-cell imaging to monitor FoxO1 localization. When parsed against human superenhancers and GWAS-derived diabetes susceptibility alleles, this map revealed a conserved superenhancer in , a gene encoding a β cell/stomach-enriched nuclear protein of unknown function. Genetic ablation of C2cd4a in β cells of mice phenocopied the metabolic abnormalities of human carriers of -linked polymorphisms, resulting in impaired insulin secretion during glucose tolerance tests as well as hyperglycemic clamps. C2CD4A regulates glycolytic genes, and notably represses key β cell "disallowed" genes, such as  We propose that  is a transcriptional coregulator of the glycolytic pathway whose dysfunction accounts for the diabetes susceptibility associated with the chromosome 15 GWAS locus.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31451658,

title = {Circadian lipid synthesis in brown fat maintains murine body temperature during chronic cold},

author = {Marine Adlanmerini and Bryce J Carpenter and Jarrett R Remsberg and Yann Aubert and Lindsey C Peed and Hannah J Richter and Mitchell A Lazar},

doi = {10.1073/pnas.1909883116},

issn = {1091-6490},

year  = {2019},

date = {2019-09-01},

journal = {Proc Natl Acad Sci U S A},

volume = {116},

number = {37},

pages = {18691--18699},

abstract = {Ambient temperature influences the molecular clock and lipid metabolism, but the impact of chronic cold exposure on circadian lipid metabolism in thermogenic brown adipose tissue (BAT) has not been studied. Here we show that during chronic cold exposure (1 wk at 4 °C), genes controlling de novo lipogenesis (DNL) including , the master transcriptional regulator of DNL, acquired high-amplitude circadian rhythms in thermogenic BAT. These conditions activated mechanistic target of rapamycin 1 (mTORC1), an inducer of  expression, and engaged circadian transcriptional repressors REV-ERBα and β as rhythmic regulators of  in BAT. SREBP was required in BAT for the thermogenic response to norepinephrine, and depletion of SREBP prevented maintenance of body temperature both during circadian cycles as well as during fasting of chronically cold mice. By contrast, deletion of REV-ERBα and β in BAT allowed mice to maintain their body temperature in chronic cold. Thus, the environmental challenge of prolonged noncircadian exposure to cold temperature induces circadian induction of SREBP1 that drives fuel synthesis in BAT and is necessary to maintain circadian body temperature during chronic cold exposure. The requirement for BAT fatty acid synthesis has broad implications for adaptation to cold.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31257031,

title = {Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner},

author = {Diego Adhemar Jaitin and Lorenz Adlung and Christoph A Thaiss and Assaf Weiner and Baoguo Li and Hélène Descamps and Patrick Lundgren and Camille Bleriot and Zhaoyuan Liu and Aleksandra Deczkowska and Hadas Keren-Shaul and Eyal David and Niv Zmora and Shai Meron Eldar and Nir Lubezky and Oren Shibolet and David A Hill and Mitchell A Lazar and Marco Colonna and Florent Ginhoux and Hagit Shapiro and Eran Elinav and Ido Amit},

doi = {10.1016/j.cell.2019.05.054},

issn = {1097-4172},

year  = {2019},

date = {2019-07-01},

journal = {Cell},

volume = {178},

number = {3},

pages = {686--698.e14},

abstract = {Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2 lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hypercholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31127047,

title = {SR9009 has REV-ERB-independent effects on cell proliferation and metabolism},

author = {Pieterjan Dierickx and Matthew J Emmett and Chunjie Jiang and Kahealani Uehara and Manlu Liu and Marine Adlanmerini and Mitchell A Lazar},

doi = {10.1073/pnas.1904226116},

issn = {1091-6490},

year  = {2019},

date = {2019-06-01},

journal = {Proc Natl Acad Sci U S A},

volume = {116},

number = {25},

pages = {12147--12152},

abstract = {The nuclear receptors REV-ERBα and -β link circadian rhythms and metabolism. Like other nuclear receptors, REV-ERB activity can be regulated by ligands, including naturally occurring heme. A putative ligand, SR9009, has been reported to elicit a range of beneficial effects in healthy as well as diseased animal models and cell systems. However, the direct involvement of REV-ERBs in these effects of SR9009 has not been thoroughly assessed, as experiments were not performed in the complete absence of both proteins. Here, we report the generation of a mouse model for conditional genetic deletion of REV-ERBα and -β. We show that SR9009 can decrease cell viability, rewire cellular metabolism, and alter gene transcription in hepatocytes and embryonic stem cells lacking both REV-ERBα and -β. Thus, the effects of SR9009 cannot be used solely as surrogate for REV-ERB activity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31120862,

title = {Induction of α cell-restricted Gc in dedifferentiating β cells contributes to stress-induced β-cell dysfunction},

author = {Taiyi Kuo and Manashree Damle and Bryan J González and Dieter Egli and Mitchell A Lazar and Domenico Accili},

doi = {10.1172/jci.insight.128351},

issn = {2379-3708},

year  = {2019},

date = {2019-05-01},

journal = {JCI Insight},

volume = {5},

number = {13},

abstract = {Diabetic β cell failure is associated with β cell dedifferentiation. To identify effector genes of dedifferentiation, we integrated analyses of histone methylation as a surrogate of gene activation status and RNA expression in β cells sorted from mice with multiparity-induced diabetes. Interestingly, only a narrow subset of genes demonstrated concordant changes to histone methylation and RNA levels in dedifferentiating β cells. Notable among them was the α cell signature gene Gc, encoding a vitamin D-binding protein. While diabetes was associated with Gc induction, Gc-deficient islets did not induce β cell dedifferentiation markers and maintained normal ex vivo insulin secretion in the face of metabolic challenge. Moreover, Gc-deficient mice exhibited a more robust insulin secretory response than normal controls during hyperglycemic clamps. The data are consistent with a functional role of Gc activation in β cell dysfunction, and indicate that multiparity-induced diabetes is associated with altered β cell fate.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30842678,

title = {Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity},

author = {Olof S Dallner and Jill M Marinis and Yi-Hsueh Lu and Kivanc Birsoy and Emory Werner and Gulya Fayzikhodjaeva and Brian D Dill and Henrik Molina and Arden Moscati and Zoltán Kutalik and Pedro Marques-Vidal and Tuomas O Kilpeläinen and Niels Grarup and Allan Linneberg and Yinxin Zhang and Roger Vaughan and Ruth J F Loos and Mitchell A Lazar and Jeffrey M Friedman},

doi = {10.1038/s41591-019-0370-1},

issn = {1546-170X},

year  = {2019},

date = {2019-03-01},

journal = {Nat Med},

volume = {25},

number = {3},

pages = {507--516},

abstract = {Quantitative changes in leptin concentration lead to alterations in food intake and body weight, but the regulatory mechanisms that control leptin gene expression are poorly understood. Here we report that fat-specific and quantitative leptin expression is controlled by redundant cis elements and trans factors interacting with the proximal promoter together with a long noncoding RNA (lncOb). Diet-induced obese mice lacking lncOb show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment, whereas control mice do not. Consistent with this finding, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms (SNPs) in the region of human lncOb with lower plasma leptin levels and obesity. These results show that reduced leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity and provide a framework for elucidating the pathogenic mechanism in the subset of obese patients with low endogenous leptin levels.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30390028,

title = {Integrative regulation of physiology by histone deacetylase 3},

author = {Matthew J Emmett and Mitchell A Lazar},

doi = {10.1038/s41580-018-0076-0},

issn = {1471-0080},

year  = {2019},

date = {2019-02-01},

journal = {Nat Rev Mol Cell Biol},

volume = {20},

number = {2},

pages = {102--115},

abstract = {Cell-type-specific gene expression is physiologically modulated by the binding of transcription factors to genomic enhancer sequences, to which chromatin modifiers such as histone deacetylases (HDACs) are recruited. Drugs that inhibit HDACs are in clinical use but lack specificity. HDAC3 is a stoichiometric component of nuclear receptor co-repressor complexes whose enzymatic activity depends on this interaction. HDAC3 is required for many aspects of mammalian development and physiology, for example, for controlling metabolism and circadian rhythms. In this Review, we discuss the mechanisms by which HDAC3 regulates cell type-specific enhancers, the structure of HDAC3 and its function as part of nuclear receptor co-repressors, its enzymatic activity and its post-translational modifications. We then discuss the plethora of tissue-specific physiological functions of HDAC3.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30639037,

title = {Patient Adipose Stem Cell-Derived Adipocytes Reveal Genetic Variation that Predicts Antidiabetic Drug Response},

author = {Wenxiang Hu and Chunjie Jiang and Dongyin Guan and Pieterjan Dierickx and Rong Zhang and Arden Moscati and Girish N Nadkarni and David J Steger and Ruth J F Loos and Cheng Hu and Weiping Jia and Raymond E Soccio and Mitchell A Lazar},

doi = {10.1016/j.stem.2018.11.018},

issn = {1875-9777},

year  = {2019},

date = {2019-02-01},

journal = {Cell Stem Cell},

volume = {24},

number = {2},

pages = {299--308.e6},

abstract = {Thiazolidinedione drugs (TZDs) target the transcriptional activity of peroxisome proliferator activated receptor γ (PPARγ) to reverse insulin resistance in type 2 diabetes, but side effects limit their clinical use. Here, using human adipose stem cell-derived adipocytes, we demonstrate that SNPs were enriched at sites of patient-specific PPARγ binding, which correlated with the individual-specific effects of the TZD rosiglitazone (rosi) on gene expression. Rosi induction of ABCA1, which regulates cholesterol metabolism, was dependent upon SNP rs4743771, which modulated PPARγ binding by influencing the genomic occupancy of its cooperating factor, NFIA. Conversion of rs4743771 from the inactive SNP allele to the active one by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated editing rescued PPARγ binding and rosi induction of ABCA1 expression. Moreover, rs4743771 is a major determinant of undesired serum cholesterol increases in rosi-treated diabetics. These data highlight human genetic variation that impacts PPARγ genomic occupancy and patient responses to antidiabetic drugs, with implications for developing personalized therapies for metabolic disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30463906,

title = {Toxicity of overexpressed MeCP2 is independent of HDAC3 activity},

author = {Martha V Koerner and Laura FitzPatrick and Jim Selfridge and Jacky Guy and Dina De Sousa and Rebekah Tillotson and Alastair Kerr and Zheng Sun and Mitchell A Lazar and Matthew J Lyst and Adrian Bird},

doi = {10.1101/gad.320325.118},

issn = {1549-5477},

year  = {2018},

date = {2018-12-01},

journal = {Genes Dev},

volume = {32},

number = {23-24},

pages = {1514--1524},

abstract = {Duplication of the X-linked  gene causes a severe neurological syndrome whose molecular basis is poorly understood. To determine the contribution of known functional domains to overexpression toxicity, we engineered a mouse model that expresses wild-type or mutated MeCP2 from the  () locus in addition to the endogenous protein. Animals that expressed approximately four times the wild-type level of MeCP2 failed to survive to weaning. Strikingly, a single amino acid substitution that prevents MeCP2 from binding to the TBL1X(R1) subunit of nuclear receptor corepressor 1/2 (NCoR1/2) complexes, when expressed at equivalent high levels, was phenotypically indistinguishable from wild type, suggesting that excessive corepressor recruitment underlies toxicity. In contrast, mutations affecting the DNA-binding domain were toxic when overexpressed. As the NCoR1/2 corepressors are thought to act through histone deacetylation by histone deacetylase 3 (HDAC3), we asked whether mutations in NCoR1 and NCoR2 that drastically reduced their ability to activate this enzyme would relieve the MeCP2 overexpression phenotype. Surprisingly, severity was unaffected, indicating that the catalytic activity of HDAC3 is not the mediator of toxicity. Our findings shed light on the molecular mechanisms underlying  duplication syndrome and call for a re-evaluation of the precise biological role played by corepressor recruitment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29715048,

title = {β-Adrenergic receptors control brown adipose UCP-1 tone and cold response without affecting its circadian rhythmicity},

author = {Maria Razzoli and Matthew J Emmett and Mitchell A Lazar and Alessandro Bartolomucci},

doi = {10.1096/fj.201800452R},

issn = {1530-6860},

year  = {2018},

date = {2018-10-01},

journal = {FASEB J},

volume = {32},

number = {10},

pages = {5640--5646},

abstract = {Brown adipose tissue (BAT) thermogenic functions are primarily mediated by uncoupling protein (UCP)-1. Ucp1 gene expression is highly induced by cold temperature, via sympathetic nervous system and β-adrenergic receptors (βARs). Ucp1 is also repressed by the clock gene Rev-erbα, contributing to its circadian rhythmicity. In this study, we investigated mice lacking βARs (β-less mice) to test the relationship between βAR signaling and the BAT molecular clock. We found that in addition to controlling the induction of Ucp1 and other key BAT genes at near freezing temperatures, βARs are essential for the basal expression of BAT Ucp1 at room temperature. Remarkably, although basal Ucp1 expression is low throughout day and night in β-less mice, the circadian rhythmicity of Ucp1 and clock genes in BAT is maintained. Thus, the requirement of βAR signaling for BAT activity is independent of the circadian rhythmicity of Ucp1 expression and circadian oscillation of the molecular clock genes. On the other hand, we found that βARs are essential for the normal circadian rhythms of locomotor activity. Our results demonstrate that in addition to controlling the BAT response to extreme cold, βAR signaling is necessary to maintain basal Ucp1 tone and to couple BAT circadian rhythmicity to the central clock.-Razzoli, M., Emmett, M. J., Lazar, M. A., Bartolomucci, A. β-Adrenergic receptors control brown adipose UCP-1 tone and cold response without affecting its circadian rhythmicity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29751019,

title = {Nighttime light exposure enhances Rev-erbα-targeting microRNAs and contributes to hepatic steatosis},

author = {Patricia C Borck and Thiago M Batista and Jean F Vettorazzi and Gabriela M Soares and Camila Lubaczeuski and Dongyin Guan and Antonio C Boschero and Elaine Vieira and Mitchell A Lazar and Everardo M Carneiro},

doi = {10.1016/j.metabol.2018.05.002},

issn = {1532-8600},

year  = {2018},

date = {2018-08-01},

journal = {Metabolism},

volume = {85},

pages = {250--258},

abstract = {OBJECTIVE: The exposure to artificial light at night (ALAN) disrupts the biological rhythms and has been associated with the development of metabolic syndrome. MicroRNAs (miRNAs) display a critical role in fine-tuning the circadian system and energy metabolism. In this study, we aimed to assess whether altered miRNAs expression in the liver underlies metabolic disorders caused by disrupted biological rhythms.nnRESULTS: We found that C3H/HePas mice exposed to ALAN developed obesity, and hepatic steatosis, which was paralleled by decreased expression of Rev-erbα and up-regulation of its lipogenic targets ACL and FAS in liver. Furthermore, the expression of Rev-erbα-targeting miRNAs, miR-140-5p, 185-5p, 326-5p and 328-5p were increased in this group. Consistently, overexpression of these miRNAs in primary hepatocytes reduced Rev-erbα expression at the mRNA and protein levels. Importantly, overexpression of Rev-erbα-targeting miRNAs increased mRNA levels of Acly and Fasn.nnCONCLUSION: Thus, altered miRNAs profile is an important mechanism underlying the disruption of the peripheral clock caused by exposure to ALAN, which could lead to hepatic steatosis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30006480,

title = {PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism},

author = {Victoria L Nelson and Hoang C B Nguyen and Juan C Garcìa-Cañaveras and Erika R Briggs and Wesley Y Ho and Joanna R DiSpirito and Jill M Marinis and David A Hill and Mitchell A Lazar},

doi = {10.1101/gad.312355.118},

issn = {1549-5477},

year  = {2018},

date = {2018-08-01},

journal = {Genes Dev},

volume = {32},

number = {15-16},

pages = {1035--1044},

abstract = {The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPARγ ligand, in a PPARγ-dependent manner. Moreover, PPARγ is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARγ dramatically affects the oxidation of glutamine. Both glutamine and PPARγ have been implicated in alternative activation (AA) of macrophages, and PPARγ was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPARγ contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPARγ functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPARγ expression is itself markedly increased by IL4. This suggests that PPARγ functions at the center of a feed-forward loop that is central to AA of macrophages.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30057115,

title = {Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes},

author = {Dongyin Guan and Ying Xiong and Patricia C Borck and Cholsoon Jang and Paschalis-Thomas Doulias and Romeo Papazyan and Bin Fang and Chunjie Jiang and Yuxiang Zhang and Erika R Briggs and Wenxiang Hu and David Steger and Harry Ischiropoulos and Joshua D Rabinowitz and Mitchell A Lazar},

doi = {10.1016/j.cell.2018.06.031},

issn = {1097-4172},

year  = {2018},

date = {2018-08-01},

journal = {Cell},

volume = {174},

number = {4},

pages = {831--842.e12},

abstract = {Overnutrition disrupts circadian metabolic rhythms by mechanisms that are not well understood. Here, we show that diet-induced obesity (DIO) causes massive remodeling of circadian enhancer activity in mouse liver, triggering synchronous high-amplitude circadian rhythms of both fatty acid (FA) synthesis and oxidation. SREBP expression was rhythmically induced by DIO, leading to circadian FA synthesis and, surprisingly, FA oxidation (FAO). DIO similarly caused a high-amplitude circadian rhythm of PPARα, which was also required for FAO. Provision of a pharmacological activator of PPARα abrogated the requirement of SREBP for FAO (but not FA synthesis), suggesting that SREBP indirectly controls FAO via production of endogenous PPARα ligands. The high-amplitude rhythm of PPARα imparted time-of-day-dependent responsiveness to lipid-lowering drugs. Thus, acquisition of rhythmicity for non-core clock components PPARα and SREBP1 remodels metabolic gene transcription in response to overnutrition and enables a chronopharmacological approach to metabolic disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29757190,

title = {Reversing the curse on PPARγ},

author = {Mitchell A Lazar},

doi = {10.1172/JCI121392},

issn = {1558-8238},

year  = {2018},

date = {2018-06-01},

journal = {J Clin Invest},

volume = {128},

number = {6},

pages = {2202--2204},

abstract = {Thiazolidinediones (TZDs) are the only antidiabetic drugs that reverse insulin resistance. They have been a valuable asset in the treatment of type 2 diabetes, but their side effects have curtailed widespread use in the clinic. In this issue of the JCI, Kraakman and colleagues provide evidence that deacetylation of the nuclear receptor PPARγ improves the therapeutic index of TZDs. These findings should revitalize the quest to employ insulin sensitization as a first-line approach to managing type 2 diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29891714,

title = {A noncanonical PPARγ/RXRα-binding sequence regulates leptin expression in response to changes in adipose tissue mass},

author = {Yinxin Zhang and Olof Stefan Dallner and Tomoyoshi Nakadai and Gulya Fayzikhodjaeva and Yi-Hsueh Lu and Mitchell A Lazar and Robert G Roeder and Jeffrey M Friedman},

doi = {10.1073/pnas.1806366115},

issn = {1091-6490},

year  = {2018},

date = {2018-06-01},

journal = {Proc Natl Acad Sci U S A},

volume = {115},

number = {26},

pages = {E6039--E6047},

abstract = {Leptin expression decreases after fat loss and is increased when obesity develops, and its proper quantitative regulation is essential for the homeostatic control of fat mass. We previously reported that a distant leptin enhancer 1 (LE1), 16 kb upstream from the transcription start site (TSS), confers fat-specific expression in a bacterial artificial chromosome transgenic (BACTG) reporter mouse. However, this and the other elements that we identified do not account for the quantitative changes in leptin expression that accompany alterations of adipose mass. In this report, we used an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) to identify a 17-bp noncanonical peroxisome proliferator-activated receptor gamma (PPARγ)/retinoid X receptor alpha (RXRα)-binding site, leptin regulatory element 1 (LepRE1), within LE1, and show that it is necessary for the fat-regulated quantitative control of reporter (luciferase) expression. While BACTG reporter mice with mutations in this sequence still show fat-specific expression, luciferase is no longer decreased after food restriction and weight loss. Similarly, the increased expression of leptin reporter associated with obesity in  mice is impaired. A functionally analogous LepRE1 site is also found in a second, redundant DNA regulatory element 13 kb downstream of the TSS. These data uncouple the mechanisms conferring qualitative and quantitative expression of the leptin gene and further suggest that factor(s) that bind to LepRE1 quantitatively control leptin expression and might be components of a lipid-sensing system in adipocytes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29760084,

title = {Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue},

author = {David A Hill and Hee-Woong Lim and Yong Hoon Kim and Wesley Y Ho and Yee Hoon Foong and Victoria L Nelson and Hoang C B Nguyen and Kavya Chegireddy and Jihoon Kim and Andreas Habertheuer and Prashanth Vallabhajosyula and Taku Kambayashi and Kyoung-Jae Won and Mitchell A Lazar},

doi = {10.1073/pnas.1802611115},

issn = {1091-6490},

year  = {2018},

date = {2018-05-01},

journal = {Proc Natl Acad Sci U S A},

volume = {115},

number = {22},

pages = {E5096--E5105},

abstract = {Obesity is characterized by an accumulation of macrophages in adipose, some of which form distinct crown-like structures (CLS) around fat cells. While multiple discrete adipose tissue macrophage (ATM) subsets are thought to exist, their respective effects on adipose tissue, and the transcriptional mechanisms that underlie the functional differences between ATM subsets, are not well understood. We report that obese fat tissue of mice and humans contain multiple distinct populations of ATMs with unique tissue distributions, transcriptomes, chromatin landscapes, and functions. Mouse Ly6c ATMs reside outside of CLS and are adipogenic, while CD9 ATMs reside within CLS, are lipid-laden, and are proinflammatory. Adoptive transfer of Ly6c ATMs into lean mice activates gene programs typical of normal adipocyte physiology. By contrast, adoptive transfer of CD9 ATMs drives gene expression that is characteristic of obesity. Importantly, human adipose tissue contains similar ATM populations, including lipid-laden CD9 ATMs that increase with body mass. These results provide a higher resolution of the cellular and functional heterogeneity within ATMs and provide a framework within which to develop new immune-directed therapies for the treatment of obesity and related sequela.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29439026,

title = {Rev-erbα dynamically modulates chromatin looping to control circadian gene transcription},

author = {Yong Hoon Kim and Sajid A Marhon and Yuxiang Zhang and David J Steger and Kyoung-Jae Won and Mitchell A Lazar},

doi = {10.1126/science.aao6891},

issn = {1095-9203},

year  = {2018},

date = {2018-03-01},

journal = {Science},

volume = {359},

number = {6381},

pages = {1274--1277},

abstract = {Mammalian physiology exhibits 24-hour cyclicity due to circadian rhythms of gene expression controlled by transcription factors that constitute molecular clocks. Core clock transcription factors bind to the genome at enhancer sequences to regulate circadian gene expression, but not all binding sites are equally functional. We found that in mice, circadian gene expression in the liver is controlled by rhythmic chromatin interactions between enhancers and promoters. Rev-erbα, a core repressive transcription factor of the clock, opposes functional loop formation between Rev-erbα-regulated enhancers and circadian target gene promoters by recruitment of the NCoR-HDAC3 co-repressor complex, histone deacetylation, and eviction of the elongation factor BRD4 and the looping factor MED1. Thus, a repressive arm of the molecular clock operates by rhythmically modulating chromatin loops to control circadian gene transcription.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29133417,

title = {Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction},

author = {Jessica C Jang and Jiang Li and Luca Gambini and Hashini M Batugedara and Sandeep Sati and Mitchell A Lazar and Li Fan and Maurizio Pellecchia and Meera G Nair},

doi = {10.1073/pnas.1716015114},

issn = {1091-6490},

year  = {2017},

date = {2017-11-01},

journal = {Proc Natl Acad Sci U S A},

volume = {114},

number = {48},

pages = {E10399--E10408},

abstract = {Helminths trigger multiple immunomodulatory pathways that can protect from sepsis. Human resistin (hRetn) is an immune cell-derived protein that is highly elevated in helminth infection and sepsis. However, the function of hRetn in sepsis, or whether hRetn influences helminth protection against sepsis, is unknown. Employing hRetn-expressing transgenic mice (hTg) and recombinant hRetn, we identify a therapeutic function for hRetn in lipopolysaccharide (LPS)-induced septic shock. hRetn promoted helminth-induced immunomodulation, with increased survival of  ()-infected hTg mice after a fatal LPS dose compared with naive mice or -infected hTg mice. Employing immunoprecipitation assays, hTg mice, and human immune cell culture, we demonstrate that hRetn binds the LPS receptor Toll-like receptor 4 (TLR4) through its N terminal and modulates STAT3 and TBK1 signaling, triggering a switch from proinflammatory to anti-inflammatory responses. Further, we generate hRetn N-terminal peptides that are able to block LPS proinflammatory function. Together, our studies identify a critical role for hRetn in blocking LPS function with important clinical significance in helminth-induced immunomodulation and sepsis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29033129,

title = {Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction},

author = {Andrey Poleshko and Parisha P Shah and Mudit Gupta and Apoorva Babu and Michael P Morley and Lauren J Manderfield and Jamie L Ifkovits and Damelys Calderon and Haig Aghajanian and Javier E Sierra-Pagán and Zheng Sun and Qiaohong Wang and Li Li and Nicole C Dubois and Edward E Morrisey and Mitchell A Lazar and Cheryl L Smith and Jonathan A Epstein and Rajan Jain},

doi = {10.1016/j.cell.2017.09.018},

issn = {1097-4172},

year  = {2017},

date = {2017-10-01},

journal = {Cell},

volume = {171},

number = {3},

pages = {573--587.e14},

abstract = {Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin, and independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina. Deletion of Hdac3 in cardiac progenitor cells releases genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes; in contrast, restricting Hdac3 to the nuclear periphery rescues myogenesis in progenitors otherwise lacking Hdac3. Our results suggest that availability of genomic regions for activation by lineage-specific factors is regulated in part through dynamic chromatin-nuclear lamina interactions and that competence of a progenitor cell to respond to differentiation signals may depend upon coordinated movement of responding gene loci away from the nuclear periphery.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28916805,

title = {An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides},

author = {Sean M Armour and Jarrett R Remsberg and Manashree Damle and Simone Sidoli and Wesley Y Ho and Zhenghui Li and Benjamin A Garcia and Mitchell A Lazar},

doi = {10.1038/s41467-017-00772-5},

issn = {2041-1723},

year  = {2017},

date = {2017-09-01},

journal = {Nat Commun},

volume = {8},

number = {1},

pages = {549},

abstract = {The histone deacetylase HDAC3 is a critical mediator of hepatic lipid metabolism, and liver-specific deletion of HDAC3 leads to fatty liver. To elucidate the underlying mechanism, here we report a method of cross-linking followed by mass spectrometry to define a high-confidence HDAC3 interactome in vivo that includes the canonical NCoR-HDAC3 complex as well as Prospero-related homeobox 1 protein (PROX1). HDAC3 and PROX1 co-localize extensively on the mouse liver genome, and are co-recruited by hepatocyte nuclear factor 4α (HNF4α). The HDAC3-PROX1 module controls the expression of a gene program regulating lipid homeostasis, and hepatic-specific ablation of either component increases triglyceride content in liver. These findings underscore the importance of specific combinations of transcription factors and coregulators in the fine tuning of organismal metabolism.HDAC3 is a critical mediator of hepatic lipid metabolism and its loss leads to fatty liver. Here, the authors characterize the liver HDAC3 interactome in vivo, provide evidence that HDAC3 interacts with PROX1, and show that HDAC3 and PROX1 control expression of genes regulating lipid homeostasis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28416361,

title = {Unraveling the Regulation of Hepatic Metabolism by Insulin},

author = {Paul M Titchenell and Mitchell A Lazar and Morris J Birnbaum},

doi = {10.1016/j.tem.2017.03.003},

issn = {1879-3061},

year  = {2017},

date = {2017-07-01},

journal = {Trends Endocrinol Metab},

volume = {28},

number = {7},

pages = {497--505},

abstract = {During insulin-resistant states such as type 2 diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production but promotes lipid synthesis leading to hyperglycemia and hypertriglyceridemia. Defining the downstream signaling pathways underlying the control of hepatic metabolism by insulin is necessary for understanding both normal physiology and the pathogenesis of metabolic disease. We summarize recent literature highlighting the importance of both hepatic and extrahepatic mechanisms in insulin regulation of liver glucose and lipid metabolism. We posit that a failure of insulin to inappropriately regulate liver metabolism during T2DM is not exclusively from an inherent defect in canonical liver insulin signaling but is instead due to a combination of hyperinsulinemia, altered substrate supply, and the input of several extrahepatic signals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28614293,

title = {Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge},

author = {Matthew J Emmett and Hee-Woong Lim and Jennifer Jager and Hannah J Richter and Marine Adlanmerini and Lindsey C Peed and Erika R Briggs and David J Steger and Tao Ma and Carrie A Sims and Joseph A Baur and Liming Pei and Kyoung-Jae Won and Patrick Seale and Zachary Gerhart-Hines and Mitchell A Lazar},

doi = {10.1038/nature22819},

issn = {1476-4687},

year  = {2017},

date = {2017-06-01},

journal = {Nature},

volume = {546},

number = {7659},

pages = {544--548},

abstract = {Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor, it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28747429,

title = {The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ},

author = {Yuxiang Zhang and Romeo Papazyan and Manashree Damle and Bin Fang and Jennifer Jager and Dan Feng and Lindsey C Peed and Dongyin Guan and Zheng Sun and Mitchell A Lazar},

doi = {10.1101/gad.302323.117},

issn = {1549-5477},

year  = {2017},

date = {2017-06-01},

journal = {Genes Dev},

volume = {31},

number = {12},

pages = {1202--1211},

abstract = {Liver lipid metabolism is under intricate temporal control by both the circadian clock and feeding. The interplay between these two mechanisms is not clear. Here we show that liver-specific depletion of nuclear receptors RORα and RORγ, key components of the molecular circadian clock, up-regulate expression of lipogenic genes only under fed conditions at Zeitgeber time 22 (ZT22) but not under fasting conditions at ZT22 or ad libitum conditions at ZT10. RORα/γ controls circadian expression of , which keeps feeding-induced SREBP1c activation under check. Loss of RORα/γ causes overactivation of the SREBP-dependent lipogenic response to feeding, exacerbating diet-induced hepatic steatosis. These findings thus establish ROR/INSIG2/SREBP as a molecular pathway by which circadian clock components anticipatorily regulate lipogenic responses to feeding. This highlights the importance of time of day as a consideration in the treatment of liver metabolic disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28240605,

title = {Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice},

author = {Raymond E Soccio and Zhenghui Li and Eric R Chen and Yee Hoon Foong and Kiara K Benson and Joanna R Dispirito and Shannon E Mullican and Matthew J Emmett and Erika R Briggs and Lindsey C Peed and Richard K Dzeng and Carlos J Medina and Jennifer F Jolivert and Megan Kissig and Satyajit R Rajapurkar and Manashree Damle and Hee-Woong Lim and Kyoung-Jae Won and Patrick Seale and David J Steger and Mitchell A Lazar},

doi = {10.1172/JCI91211},

issn = {1558-8238},

year  = {2017},

date = {2017-04-01},

journal = {J Clin Invest},

volume = {127},

number = {4},

pages = {1451--1462},

abstract = {Obesity causes insulin resistance, and PPARγ ligands such as rosiglitazone are insulin sensitizing, yet the mechanisms remain unclear. In C57BL/6 (B6) mice, obesity induced by a high-fat diet (HFD) has major effects on visceral epididymal adipose tissue (eWAT). Here, we report that HFD-induced obesity in B6 mice also altered the activity of gene regulatory elements and genome-wide occupancy of PPARγ. Rosiglitazone treatment restored insulin sensitivity in obese B6 mice, yet, surprisingly, had little effect on gene expression in eWAT. However, in subcutaneous inguinal fat (iWAT), rosiglitazone markedly induced molecular signatures of brown fat, including the key thermogenic gene Ucp1. Obesity-resistant 129S1/SvImJ mice (129 mice) displayed iWAT browning, even in the absence of rosiglitazone. The 129 Ucp1 locus had increased PPARγ binding and gene expression that were preserved in the iWAT of B6x129 F1-intercrossed mice, with an imbalance favoring the 129-derived alleles, demonstrating a cis-acting genetic difference. Thus, B6 mice have genetically defective Ucp1 expression in iWAT. However, when Ucp1 was activated by rosiglitazone, or by iWAT browning in cold-exposed or young mice, expression of the B6 version of Ucp1 was no longer defective relative to the 129 version, indicating epigenomic rescue. These results provide a framework for understanding how environmental influences like drugs can affect the epigenome and potentially rescue genetically determined disease phenotypes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28368290,

title = {Maturing of the nuclear receptor family},

author = {Mitchell A Lazar},

doi = {10.1172/JCI92949},

issn = {1558-8238},

year  = {2017},

date = {2017-04-01},

journal = {J Clin Invest},

volume = {127},

number = {4},

pages = {1123--1125},

abstract = {Members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors play important roles in reproduction, development, and physiology. In humans, genetic mutations in NRs are causes of rare diseases, while hormones and drugs that target NRs are in widespread therapeutic use. The present issue of the JCI includes a series of Review articles focused on specific NRs and their wide range of biological functions. Here I reflect on the past, present, and potential future highlights of research on the NR superfamily.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27991918,

title = {Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion},

author = {Sungguan Hong and Wenjun Zhou and Bin Fang and Wenyun Lu and Emanuele Loro and Manashree Damle and Guolian Ding and Jennifer Jager and Sisi Zhang and Yuxiang Zhang and Dan Feng and Qingwei Chu and Brian D Dill and Henrik Molina and Tejvir S Khurana and Joshua D Rabinowitz and Mitchell A Lazar and Zheng Sun},

doi = {10.1038/nm.4245},

issn = {1546-170X},

year  = {2017},

date = {2017-02-01},

journal = {Nat Med},

volume = {23},

number = {2},

pages = {223--234},

abstract = {Type 2 diabetes and insulin resistance are associated with reduced glucose utilization in the muscle and poor exercise performance. Here we find that depletion of the epigenome modifier histone deacetylase 3 (HDAC3) specifically in skeletal muscle causes severe systemic insulin resistance in mice but markedly enhances endurance and resistance to muscle fatigue, despite reducing muscle force. This seemingly paradoxical phenotype is due to lower glucose utilization and greater lipid oxidation in HDAC3-depleted muscles, a fuel switch caused by the activation of anaplerotic reactions driven by AMP deaminase 3 (Ampd3) and catabolism of branched-chain amino acids. These findings highlight the pivotal role of amino acid catabolism in muscle fatigue and type 2 diabetes pathogenesis. Further, as genome occupancy of HDAC3 in skeletal muscle is controlled by the circadian clock, these results delineate an epigenomic regulatory mechanism through which the circadian clock governs skeletal muscle bioenergetics. These findings suggest that physical exercise at certain times of the day or pharmacological targeting of HDAC3 could potentially be harnessed to alter systemic fuel metabolism and exercise performance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28059714,

title = {Regeneration of fat cells from myofibroblasts during wound healing},

author = {Maksim V Plikus and Christian F Guerrero-Juarez and Mayumi Ito and Yun Rose Li and Priya H Dedhia and Ying Zheng and Mengle Shao and Denise L Gay and Raul Ramos and Tsai-Ching Hsi and Ji Won Oh and Xiaojie Wang and Amanda Ramirez and Sara E Konopelski and Arijh Elzein and Anne Wang and Rarinthip June Supapannachart and Hye-Lim Lee and Chae Ho Lim and Arben Nace and Amy Guo and Elsa Treffeisen and Thomas Andl and Ricardo N Ramirez and Rabi Murad and Stefan Offermanns and Daniel Metzger and Pierre Chambon and Alan D Widgerow and Tai-Lan Tuan and Ali Mortazavi and Rana K Gupta and Bruce A Hamilton and Sarah E Millar and Patrick Seale and Warren S Pear and Mitchell A Lazar and George Cotsarelis},

doi = {10.1126/science.aai8792},

issn = {1095-9203},

year  = {2017},

date = {2017-02-01},

journal = {Science},

volume = {355},

number = {6326},

pages = {748--752},

abstract = {Although regeneration through the reprogramming of one cell lineage to another occurs in fish and amphibians, it has not been observed in mammals. We discovered in the mouse that during wound healing, adipocytes regenerate from myofibroblasts, a cell type thought to be differentiated and nonadipogenic. Myofibroblast reprogramming required neogenic hair follicles, which triggered bone morphogenetic protein (BMP) signaling and then activation of adipocyte transcription factors expressed during development. Overexpression of the BMP antagonist Noggin in hair follicles or deletion of the BMP receptor in myofibroblasts prevented adipocyte formation. Adipocytes formed from human keloid fibroblasts either when treated with BMP or when placed with human hair follicles in vitro Thus, we identify the myofibroblast as a plastic cell type that may be manipulated to treat scars in humans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28123935,

title = {Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion},

author = {Jarrett R Remsberg and Benjamin N Ediger and Wesley Y Ho and Manashree Damle and Zhenghui Li and Christopher Teng and Cristina Lanzillotta and Doris A Stoffers and Mitchell A Lazar},

doi = {10.1016/j.molmet.2016.11.007},

issn = {2212-8778},

year  = {2017},

date = {2017-01-01},

journal = {Mol Metab},

volume = {6},

number = {1},

pages = {30--37},

abstract = {OBJECTIVE: Histone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice.nnMETHODS: An HDAC3 β-cell specific knockout was generated in adult ERT transgenic mice using the Cre-loxP system. Induction of HDAC3 deletion was initiated at 8 weeks of age with administration of tamoxifen in corn oil (2 mg/day for 5 days). Mice were assayed for glucose tolerance, glucose-stimulated insulin secretion, and islet function 2 weeks after induction of the knockout. Transcriptional functions of HDAC3 were assessed by ChIP-seq as well as RNA-seq comparing control and β-cell knockout islets.nnRESULTS: HDAC3 β-cell specific knockout (HDAC3βKO) did not increase total pancreatic insulin content or β-cell mass. However, HDAC3βKO mice demonstrated markedly improved glucose tolerance. This improved glucose metabolism coincided with increased basal and glucose-stimulated insulin secretion  as well as in isolated islets. Cistromic and transcriptomic analyses of pancreatic islets revealed that HDAC3 regulates multiple genes that contribute to glucose-stimulated insulin secretion.nnCONCLUSIONS: HDAC3 plays an important role in regulating insulin secretion , and therapeutic intervention may improve glucose homeostasis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27866836,

title = {Physiological Suppression of Lipotoxic Liver Damage by Complementary Actions of HDAC3 and SCAP/SREBP},

author = {Romeo Papazyan and Zheng Sun and Yong Hoon Kim and Paul M Titchenell and David A Hill and Wenyun Lu and Manashree Damle and Min Wan and Yuxiang Zhang and Erika R Briggs and Joshua D Rabinowitz and Mitchell A Lazar},

doi = {10.1016/j.cmet.2016.10.012},

issn = {1932-7420},

year  = {2016},

date = {2016-12-01},

journal = {Cell Metab},

volume = {24},

number = {6},

pages = {863--874},

abstract = {Liver fat accumulation precedes non-alcoholic steatohepatitis, an increasing cause of end-stage liver disease. Histone deacetylase 3 (HDAC3) is required for hepatic triglyceride homeostasis, and sterol regulatory element binding protein (SREBP) regulates the lipogenic response to feeding, but the crosstalk between these pathways is unknown. Here we show that inactivation of SREBP by hepatic deletion of SREBP cleavage activating protein (SCAP) abrogates the increase in lipogenesis caused by loss of HDAC3, but fatty acid oxidation remains defective. This combination leads to accumulation of lipid intermediates and to an energy drain that collectively cause oxidative stress, inflammation, liver damage, and, ultimately, synthetic lethality. Remarkably, this phenotype is prevented by ectopic expression of nuclear SREBP1c, revealing a surprising benefit of de novo lipogenesis and triglyceride synthesis in preventing lipotoxicity. These results demonstrate that HDAC3 and SCAP control symbiotic pathways of liver lipid metabolism that are critical for suppression of lipotoxicity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27922611,

title = {Genetic and epigenomic mechanisms of mammalian circadian transcription},

author = {Romeo Papazyan and Yuxiang Zhang and Mitchell A Lazar},

doi = {10.1038/nsmb.3324},

issn = {1545-9985},

year  = {2016},

date = {2016-12-01},

journal = {Nat Struct Mol Biol},

volume = {23},

number = {12},

pages = {1045--1052},

abstract = {The mammalian molecular clock comprises a complex network of transcriptional programs that integrates environmental signals with physiological pathways in a tissue-specific manner. Emerging technologies are extending knowledge of basic clock features by uncovering their underlying molecular mechanisms, thus setting the stage for a 'systems' view of the molecular clock. Here we discuss how recent data from genome-wide genetic and epigenetic studies have informed the understanding of clock function. In addition to its importance in human physiology and disease, the clock mechanism provides an ideal model to assess general principles of dynamic transcription regulation in vivo.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27885004,

title = {Circadian time signatures of fitness and disease},

author = {Joseph Bass and Mitchell A Lazar},

doi = {10.1126/science.aah4965},

issn = {1095-9203},

year  = {2016},

date = {2016-11-01},

journal = {Science},

volume = {354},

number = {6315},

pages = {994--999},

abstract = {Biological clocks are autonomous anticipatory oscillators that play a critical role in the organization and information processing from genome to whole organisms. Transformative advances into the clock system have opened insight into fundamental mechanisms through which clocks program energy transfer from sunlight into organic matter and potential energy, in addition to cell development and genotoxic stress response. The identification of clocks in nearly every single cell of the body raises questions as to how this gives rise to rhythmic physiology in multicellular organisms and how environmental signals entrain clocks to geophysical time. Here, we consider advances in understanding how regulatory networks emergent in clocks give rise to cell type-specific functions within tissues to affect homeostasis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27689007,

title = {Genetic backgrounds determine brown remodeling of white fat in rodents},

author = {Giulia Ferrannini and Maria Namwanje and Bin Fang and Manashree Damle and Dylan Li and Qiongming Liu and Mitchell A Lazar and Li Qiang},

doi = {10.1016/j.molmet.2016.08.013},

issn = {2212-8778},

year  = {2016},

date = {2016-10-01},

journal = {Mol Metab},

volume = {5},

number = {10},

pages = {948--958},

abstract = {OBJECTIVE: Genetic background largely contributes to the complexity of metabolic responses and dysfunctions. Induction of brown adipose features in white fat, known as brown remodeling, has been appreciated as a promising strategy to offset the positive energy balance in obesity and further to improve metabolism. Here we address the effects of genetic background on this process.nnMETHODS: We investigated browning remodeling in a depot-specific manner by comparing the response of C57BL/6J, 129/Sv and FVB/NJ mouse strains to cold.nnRESULTS: Surprisingly, 129/Sv and FVB/NJ mice showed distinct brown remodeling features despite their similar resistance to metabolic disorders in comparison to the obesity-prone C57BL/6J mice. FVB/NJ mice demonstrated a preference of brown remodeling in inguinal subcutaneous white adipose tissue (iWAT), whereas 129/Sv mice displayed robust brown remodeling in visceral epididymal fat (eWAT). We further compared gene expression in different depots by RNA-sequencing and identified Hoxc10 as a novel "brake" of brown remodeling in iWAT.nnCONCLUSION: Rodent genetic background determines the brown remodeling of different white fat depots. This study provides new insights into the role of genetic variation in fat remodeling in susceptibility to metabolic diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27333189,

title = {Lactate Dehydrogenase C Produces S-2-Hydroxyglutarate in Mouse Testis},

author = {Xin Teng and Matthew J Emmett and Mitchell A Lazar and Erwin Goldberg and Joshua D Rabinowitz},

doi = {10.1021/acschembio.6b00290},

issn = {1554-8937},

year  = {2016},

date = {2016-09-01},

journal = {ACS Chem Biol},

volume = {11},

number = {9},

pages = {2420--2427},

abstract = {Metabolomics is a valuable tool for studying tissue- and organism-specific metabolism. In normal mouse testis, we found 70 μM S-2-hydroxyglutarate (2HG), more than 10-fold greater than in other tissues. S-2HG is a competitive inhibitor of α-ketoglutarate-dependent demethylation enzymes and can alter histone or DNA methylation. To identify the source of testis S-2HG, we fractionated testis extracts and identified the fractions that actively produced S-2HG. Through a combination of ion exchange and size exclusion chromatography, we enriched a single active protein, the lactate dehydrogenase isozyme LDHC, which is primarily expressed in testis. At neutral pH, recombinant mouse LDHC rapidly converted both pyruvate into lactate and α-ketoglutarate into S-2HG, whereas recombinant human LDHC only produced lactate. Rapid S-2HG production by LDHC depends on amino acids 100-102 being Met-Val-Ser, a sequence that occurs only in the rodent protein. Other mammalian LDH can also produce some S-2HG, but at acidic pH. Thus, polymorphisms in the Ldhc gene control testis levels of S-2HG, and thereby epigenetics, across mammals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27445394,

title = {HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms},

author = {Yuxiang Zhang and Bin Fang and Manashree Damle and Dongyin Guan and Zhenghui Li and Yong Hoon Kim and Maureen Gannon and Mitchell A Lazar},

doi = {10.1101/gad.281972.116},

issn = {1549-5477},

year  = {2016},

date = {2016-07-01},

journal = {Genes Dev},

volume = {30},

number = {14},

pages = {1636--1644},

abstract = {Hepatocyte nuclear factor 6 (HNF6) is required for liver development, but its role in adult liver metabolism is not known. Here we show that deletion of HNF6 in livers of adult C57Bl/6 mice leads to hepatic steatosis in mice fed normal laboratory chow. Although HNF6 is known mainly as a transcriptional activator, hepatic loss of HNF6 up-regulated many lipogenic genes bound directly by HNF6. Many of these genes are targets of the circadian nuclear receptor Rev-erbα, and binding of Rev-erbα at these sites was lost when HNF6 was ablated in the liver. While HNF6 and Rev-erbα coordinately regulate hepatic lipid metabolism, each factor also affects additional gene sets independently. These findings highlight a novel mechanism of transcriptional repression by HNF6 and demonstrate how overlapping and distinct mechanisms of transcription factor function contribute to the integrated physiology of the liver.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27326936,

title = {Hdac3 Interaction with p300 Histone Acetyltransferase Regulates the Oligodendrocyte and Astrocyte Lineage Fate Switch},

author = {Liguo Zhang and Xuelian He and Lei Liu and Minqing Jiang and Chuntao Zhao and Haibo Wang and Danyang He and Tao Zheng and Xianyao Zhou and Aishlin Hassan and Zhixing Ma and Mei Xin and Zheng Sun and Mitchell A Lazar and Steven A Goldman and Eric N Olson and Q Richard Lu},

doi = {10.1016/j.devcel.2016.06.004},

issn = {1878-1551},

year  = {2016},

date = {2016-06-01},

urldate = {2016-06-01},

journal = {Dev Cell},

volume = {37},

number = {6},

pages = {582},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27002153,

title = {The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling},

author = {Jennifer Jager and Fenfen Wang and Bin Fang and Hee-Woong Lim and Lindsey C Peed and David J Steger and Kyoung-Jae Won and Alexei Kharitonenkov and Andrew C Adams and Mitchell A Lazar},

doi = {10.1074/jbc.M116.719120},

issn = {1083-351X},

year  = {2016},

date = {2016-05-01},

journal = {J Biol Chem},

volume = {291},

number = {20},

pages = {10867--10875},

abstract = {FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erbα, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erbα for Rev-erbα-binding sites identified βKlotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erbα in white adipose tissue but not liver. Rev-erbα ablation led to the robust elevated expression of βKlotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Rev-erbα. A major Rev-erbα-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) γ, which regulates its activity in the opposite direction. These findings establish Rev-erbα as a specific modulator of FGF21 signaling in adipose tissue.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26832331,

title = {HDAC3-Dependent Epigenetic Pathway Controls Lung Alveolar Epithelial Cell Remodeling and Spreading via miR-17-92 and TGF-β Signaling Regulation},

author = {Yi Wang and David B Frank and Michael P Morley and Su Zhou and Xiaoru Wang and Min Min Lu and Mitchell A Lazar and Edward E Morrisey},

doi = {10.1016/j.devcel.2015.12.031},

issn = {1878-1551},

year  = {2016},

date = {2016-02-01},

journal = {Dev Cell},

volume = {36},

number = {3},

pages = {303--315},

abstract = {The terminal stages of pulmonary development, called sacculation and alveologenesis, involve both differentiation of distal lung endoderm progenitors and extensive cellular remodeling of the resultant epithelial lineages. These processes are coupled with dramatic expansion of distal airspace and surface area. Despite the importance of these late developmental processes and their relation to neonatal respiratory diseases, little is understood about the molecular and cellular pathways critical for their successful completion. We show that a histone deacetylase 3 (Hdac3)-mediated epigenetic pathway is critical for the proper remodeling and expansion of the distal lung saccules into primitive alveoli. Loss of Hdac3 in the developing lung epithelium leads to a reduction of alveolar type 1 cell spreading and a disruption of lung sacculation. Hdac3 represses miR-17-92 expression, a microRNA cluster that regulates transforming growth factor β (TGF-β) signaling. De-repression of miR-17-92 in Hdac3-deficient lung epithelium results in decreased TGF-β signaling activity. Importantly, inhibition of TGF-β signaling and overexpression of miR-17-92 can phenocopy the defects observed in Hdac3 null lungs. Conversely, loss of miR-17-92 expression rescues many of the defects caused by loss of Hdac3 in the lung. These studies reveal an intricate epigenetic pathway where Hdac3 is required to repress miR-17-92 expression to allow for proper TGF-β signaling during lung sacculation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26859354,

title = {Hdac3 Interaction with p300 Histone Acetyltransferase Regulates the Oligodendrocyte and Astrocyte Lineage Fate Switch},

author = {Liguo Zhang and Xuelian He and Lei Liu and Minqing Jiang and Chuntao Zhao and Haibo Wang and Danyang He and Tao Zheng and Xianyao Zhou and Aishlin Hassan and Zhixing Ma and Mei Xin and Zheng Sun and Mitchell A Lazar and Steven A Goldman and Eric N Olson and Q Richard Lu},

doi = {10.1016/j.devcel.2016.01.002},

issn = {1878-1551},

year  = {2016},

date = {2016-02-01},

journal = {Dev Cell},

volume = {36},

number = {3},

pages = {316--330},

abstract = {Establishment and maintenance of CNS glial cell identity ensures proper brain development and function, yet the epigenetic mechanisms underlying glial fate control remain poorly understood. Here, we show that the histone deacetylase Hdac3 controls oligodendrocyte-specification gene Olig2 expression and functions as a molecular switch for oligodendrocyte and astrocyte lineage determination. Hdac3 ablation leads to a significant increase of astrocytes with a concomitant loss of oligodendrocytes. Lineage tracing indicates that the ectopic astrocytes originate from oligodendrocyte progenitors. Genome-wide occupancy analysis reveals that Hdac3 interacts with p300 to activate oligodendroglial lineage-specific genes, while suppressing astroglial differentiation genes including NFIA. Furthermore, we find that Hdac3 modulates the acetylation state of Stat3 and competes with Stat3 for p300 binding to antagonize astrogliogenesis. Thus, our data suggest that Hdac3 cooperates with p300 to prime and maintain oligodendrocyte identity while inhibiting NFIA and Stat3-mediated astrogliogenesis, and thereby regulates phenotypic commitment at the point of oligodendrocyte-astrocytic fate decision.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26387865,

title = {MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells},

author = {Brian J Altman and Annie L Hsieh and Arjun Sengupta and Saikumari Y Krishnanaiah and Zachary E Stine and Zandra E Walton and Arvin M Gouw and Anand Venkataraman and Bo Li and Pankuri Goraksha-Hicks and Sharon J Diskin and David I Bellovin and M Celeste Simon and Jeffrey C Rathmell and Mitchell A Lazar and John M Maris and Dean W Felsher and John B Hogenesch and Aalim M Weljie and Chi V Dang},

doi = {10.1016/j.cmet.2015.09.003},

issn = {1932-7420},

year  = {2015},

date = {2015-12-01},

journal = {Cell Metab},

volume = {22},

number = {6},

pages = {1009--1019},

abstract = {The MYC oncogene encodes MYC, a transcription factor that binds the genome through sites termed E-boxes (5'-CACGTG-3'), which are identical to the binding sites of the heterodimeric CLOCK-BMAL1 master circadian transcription factor. Hence, we hypothesized that ectopic MYC expression perturbs the clock by deregulating E-box-driven components of the circadian network in cancer cells. We report here that deregulated expression of MYC or N-MYC disrupts the molecular clock in vitro by directly inducing REV-ERBα to dampen expression and oscillation of BMAL1, and this could be rescued by knockdown of REV-ERB. REV-ERBα expression predicts poor clinical outcome for N-MYC-driven human neuroblastomas that have diminished BMAL1 expression, and re-expression of ectopic BMAL1 in neuroblastoma cell lines suppresses their clonogenicity. Further, ectopic MYC profoundly alters oscillation of glucose metabolism and perturbs glutaminolysis. Our results demonstrate an unsuspected link between oncogenic transformation and circadian and metabolic dysrhythmia, which we surmise to be advantageous for cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26332963,

title = {Rev-erbα and the circadian transcriptional regulation of metabolism},

author = {Z Gerhart-Hines and M A Lazar},

doi = {10.1111/dom.12510},

issn = {1463-1326},

year  = {2015},

date = {2015-09-01},

journal = {Diabetes Obes Metab},

volume = {17 Suppl 1},

number = {0 1},

pages = {12--16},

abstract = {The circadian clock orchestrates the co-ordinated rhythmicity of numerous metabolic pathways to anticipate daily and seasonal changes in energy demand. This vital physiological function is controlled by a set of individual clock components that are present in each cell of the body, and regulate each other as well as clock output genes. A key factor is the nuclear receptor, Rev-erbα, a transcriptional repressor which functions not only as a clock component but also as a modulator of metabolic programming in an array of tissues. This review explores the role of Rev-erbα in mediating this crosstalk between circadian rhythm and tissue-specific biological networks and its relevance to organismal physiology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26140591,

title = {Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo},

author = {Raymond E Soccio and Eric R Chen and Satyajit R Rajapurkar and Pegah Safabakhsh and Jill M Marinis and Joanna R Dispirito and Matthew J Emmett and Erika R Briggs and Bin Fang and Logan J Everett and Hee-Woong Lim and Kyoung-Jae Won and David J Steger and Ying Wu and Mete Civelek and Benjamin F Voight and Mitchell A Lazar},

doi = {10.1016/j.cell.2015.06.025},

issn = {1097-4172},

year  = {2015},

date = {2015-07-01},

journal = {Cell},

volume = {162},

number = {1},

pages = {33--44},

abstract = {SNPs affecting disease risk often reside in non-coding genomic regions. Here, we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for anti-diabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors and functionally regulate nearby genes whose expression is strain selective and imbalanced in heterozygous F1 mice. Moreover, genetically determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof of concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome-wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25927923,

title = {Circadian metabolism in the light of evolution},

author = {Zachary Gerhart-Hines and Mitchell A Lazar},

doi = {10.1210/er.2015-1007},

issn = {1945-7189},

year  = {2015},

date = {2015-06-01},

journal = {Endocr Rev},

volume = {36},

number = {3},

pages = {289--304},

abstract = {Circadian rhythm, or daily oscillation, of behaviors and biological processes is a fundamental feature of mammalian physiology that has developed over hundreds of thousands of years under the continuous evolutionary pressure of energy conservation and efficiency. Evolution has fine-tuned the body's clock to anticipate and respond to numerous environmental cues in order to maintain homeostatic balance and promote survival. However, we now live in a society in which these classic circadian entrainment stimuli have been dramatically altered from the conditions under which the clock machinery was originally set. A bombardment of artificial lighting, heating, and cooling systems that maintain constant ambient temperature; sedentary lifestyle; and the availability of inexpensive, high-calorie foods has threatened even the most powerful and ancient circadian programming mechanisms. Such environmental changes have contributed to the recent staggering elevation in lifestyle-influenced pathologies, including cancer, cardiovascular disease, depression, obesity, and diabetes. This review scrutinizes the role of the body's internal clocks in the hard-wiring of circadian networks that have evolved to achieve energetic balance and adaptability, and it discusses potential therapeutic strategies to reset clock metabolic control to modern time for the benefit of human health.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25957148,

title = {Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo},

author = {Hee-Woong Lim and N Henriette Uhlenhaut and Alexander Rauch and Juliane Weiner and Sabine Hübner and Norbert Hübner and Kyoung-Jae Won and Mitchell A Lazar and Jan Tuckermann and David J Steger},

doi = {10.1101/gr.188581.114},

issn = {1549-5469},

year  = {2015},

date = {2015-06-01},

journal = {Genome Res},

volume = {25},

number = {6},

pages = {836--844},

abstract = {Glucocorticoids (GCs) are commonly prescribed drugs, but their anti-inflammatory benefits are mitigated by metabolic side effects. Their transcriptional effects, including tissue-specific gene activation and repression, are mediated by the glucocorticoid receptor (GR), which is known to bind as a homodimer to a palindromic DNA sequence. Using ChIP-exo in mouse liver under endogenous corticosterone exposure, we report here that monomeric GR interaction with a half-site motif is more prevalent than homodimer binding. Monomers colocalize with lineage-determining transcription factors in both liver and primary macrophages, and the GR half-site motif drives transcription, suggesting that monomeric binding is fundamental to GR's tissue-specific functions. In response to exogenous GC in vivo, GR dimers assemble on chromatin near ligand-activated genes, concomitant with monomer evacuation of sites near repressed genes. Thus, pharmacological GCs mediate gene expression by favoring GR homodimer occupancy at classic palindromic sites at the expense of monomeric binding. The findings have important implications for improving therapies that target GR.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26044300,

title = {GENE REGULATION. Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock},

author = {Yuxiang Zhang and Bin Fang and Matthew J Emmett and Manashree Damle and Zheng Sun and Dan Feng and Sean M Armour and Jarrett R Remsberg and Jennifer Jager and Raymond E Soccio and David J Steger and Mitchell A Lazar},

doi = {10.1126/science.aab3021},

issn = {1095-9203},

year  = {2015},

date = {2015-06-01},

journal = {Science},

volume = {348},

number = {6242},

pages = {1488--1492},

abstract = {Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erbα, a transcription factor (TF) that functions both as a core repressive component of the cell-autonomous clock and as a regulator of metabolic genes. Here, we show that Rev-erbα modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erbα to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erbα regulates metabolic genes primarily by recruiting the HDAC3 co-repressor to sites to which it is tethered by cell type-specific transcription factors. Thus, direct competition between Rev-erbα and ROR TFs provides a universal mechanism for self-sustained control of the molecular clock across all tissues, whereas Rev-erbα uses lineage-determining factors to convey a tissue-specific epigenomic rhythm that regulates metabolism tailored to the specific need of that tissue.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26111340,

title = {ATF4 licenses C/EBPβ activity in human mesenchymal stem cells primed for adipogenesis},

author = {Daniel M Cohen and Kyoung-Jae Won and Nha Nguyen and Mitchell A Lazar and Christopher S Chen and David J Steger},

doi = {10.7554/eLife.06821},

issn = {2050-084X},

year  = {2015},

date = {2015-06-01},

journal = {Elife},

volume = {4},

pages = {e06821},

abstract = {A well-established cascade of transcription factor (TF) activity orchestrates adipogenesis in response to chemical cues, yet how cell-intrinsic determinants of differentiation such as cell shape and/or seeding density inform this transcriptional program remain enigmatic. Here, we uncover a novel mechanism licensing transcription in human mesenchymal stem cells (hMSCs) adipogenically primed by confluence. Prior to adipogenesis, confluency promotes heterodimer recruitment of the bZip TFs C/EBPβ and ATF4 to a non-canonical C/EBP DNA sequence. ATF4 depletion decreases both cell-density-dependent transcription and adipocyte differentiation. Global profiling in hMSCs and a novel cell-free assay reveals that ATF4 requires C/EBPβ for genomic binding at a motif distinct from that bound by the C/EBPβ homodimer. Our observations demonstrate that C/EBPβ bridges the transcriptional programs in naïve, confluent cells and early differentiating pre-adipocytes. Moreover, they suggest that homo- and heterodimer formation poise C/EBPβ to execute diverse and stage-specific transcriptional programs by exploiting an expanded motif repertoire.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25644604,

title = {PRDM16 binds MED1 and controls chromatin architecture to determine a brown fat transcriptional program},

author = {Matthew J Harms and Hee-Woong Lim and Yugong Ho and Suzanne N Shapira and Jeff Ishibashi and Sona Rajakumari and David J Steger and Mitchell A Lazar and Kyoung-Jae Won and Patrick Seale},

doi = {10.1101/gad.252734.114},

issn = {1549-5477},

year  = {2015},

date = {2015-02-01},

journal = {Genes Dev},

volume = {29},

number = {3},

pages = {298--307},

abstract = {PR (PRD1-BF1-RIZ1 homologous) domain-containing 16 (PRDM16) drives a brown fat differentiation program, but the mechanisms by which PRDM16 activates brown fat-selective genes have been unclear. Through chromatin immunoprecipitation (ChIP) followed by deep sequencing (ChIP-seq) analyses in brown adipose tissue (BAT), we reveal that PRDM16 binding is highly enriched at a broad set of brown fat-selective genes. Importantly, we found that PRDM16 physically binds to MED1, a component of the Mediator complex, and recruits it to superenhancers at brown fat-selective genes. PRDM16 deficiency in BAT reduces MED1 binding at PRDM16 target sites and causes a fundamental change in chromatin architecture at key brown fat-selective genes. Together, these data indicate that PRDM16 controls chromatin architecture and superenhancer activity in BAT.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25568944,

title = {Macrophage-derived human resistin is induced in multiple helminth infections and promotes inflammatory monocytes and increased parasite burden},

author = {Jessica C Jang and Gang Chen and Spencer H Wang and Mark A Barnes and Josiah I Chung and Mali Camberis and Graham Le Gros and Philip J Cooper and Cathy Steel and Thomas B Nutman and Mitchell A Lazar and Meera G Nair},

doi = {10.1371/journal.ppat.1004579},

issn = {1553-7374},

year  = {2015},

date = {2015-01-01},

journal = {PLoS Pathog},

volume = {11},

number = {1},

pages = {e1004579},

abstract = {Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26370410,

title = {Dissecting the Rev-erbα Cistrome and the Mechanisms Controlling Circadian Transcription in Liver},

author = {Bin Fang and Mitchell A Lazar},

doi = {10.1101/sqb.2015.80.027508},

issn = {1943-4456},

year  = {2015},

date = {2015-01-01},

journal = {Cold Spring Harb Symp Quant Biol},

volume = {80},

pages = {233--238},

abstract = {Circadian clocks maintain whole-body metabolic homeostasis by coordinating rhythmic gene expression in multiple tissues. Core clock regulators sustain their own oscillation and confer expression rhythmicity on clock-controlled genes (CCGs). Our unbiased examination of enhancer RNA (eRNA) transcription around the clock in mouse liver identified functional enhancers of circadian genes driven by phase-specific transcription factors (TFs). Rev-erbα emerged as a primary driver of circadian enhancers, leading to oscillating gene expression in opposite phases through direct and indirect regulation. Among Rev-erbα target genes were core clock components and metabolic CCGs. Oscillation of clock genes was enforced by direct competition between Rev-erbα and RORα for binding to cognate motifs in the genome, whereas metabolic CCGs were governed by recruitment of the NCoR/HDAC3 complex to enhancers where Rev-erbα is tethered by tissue-specific TFs. The DNA sequence-mediated competition between Rev-erbα and RORα ensures consistent clock control across all tissues. In contrast, the tethered binding mechanism is tissue-specific and thus allows Rev-erbα to dictate an epigenomic rhythm tailored to the specific need of that tissue. Therefore, discrete modes of recruitment allow Rev-erbα to link the clock to cell-specific functions, including metabolism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25383539,

title = {Nutrient-sensing nuclear receptors coordinate autophagy},

author = {Jae Man Lee and Martin Wagner and Rui Xiao and Kang Ho Kim and Dan Feng and Mitchell A Lazar and David D Moore},

doi = {10.1038/nature13961},

issn = {1476-4687},

year  = {2014},

date = {2014-12-01},

journal = {Nature},

volume = {516},

number = {7529},

pages = {112--115},

abstract = {Autophagy is an evolutionarily conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis. Its acute regulation by nutrient-sensing signalling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors peroxisome proliferator-activated receptor-α (PPARα) and farnesoid X receptor (FXR) are activated in the fasted and fed liver, respectively. Here we show that both PPARα and FXR regulate hepatic autophagy in mice. Pharmacological activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (Ppara(-/-), also known as Nr1c1(-/-)) mice, which are partially defective in the induction of autophagy by fasting. Pharmacological activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (Fxr(-/-), also known as Nr1h4(-/-)) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}