@article{pmid39509517,

title = {Hepatic vagal afferents convey clock-dependent signals to regulate circadian food intake},

author = {Lauren N Woodie and Lily C Melink and Mohit Midha and Alan M de Araújo and Caroline E Geisler and Ahren J Alberto and Brianna M Krusen and Delaine M Zundell and Guillaume de Lartigue and Matthew R Hayes and Mitchell A Lazar},

doi = {10.1126/science.adn2786},

issn = {1095-9203},

year  = {2024},

date = {2024-11-01},

journal = {Science},

volume = {386},

number = {6722},

pages = {673--677},

abstract = {Circadian desynchrony induced by shiftwork or jet lag is detrimental to metabolic health, but how synchronous or desynchronous signals are transmitted among tissues is unknown. We report that liver molecular clock dysfunction is signaled to the brain through the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a homeostatic feedback signal that relies on communication between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a potential therapeutic target for obesity in the setting of chronodisruption.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38889724,

title = {Short-term cold exposure induces persistent epigenomic memory in brown fat},

author = {Shin-Ichi Inoue and Matthew J Emmett and Hee-Woong Lim and Mohit Midha and Hannah J Richter and Isaac J Celwyn and Rashid Mehmood and Maria Chondronikola and Samuel Klein and Amy K Hauck and Mitchell A Lazar},

doi = {10.1016/j.cmet.2024.05.011},

issn = {1932-7420},

year  = {2024},

date = {2024-08-01},

journal = {Cell Metab},

volume = {36},

number = {8},

pages = {1764--1778.e9},

abstract = {Deficiency of the epigenome modulator histone deacetylase 3 (HDAC3) in brown adipose tissue (BAT) impairs the ability of mice to survive in near-freezing temperatures. Here, we report that short-term exposure to mild cold temperature (STEMCT: 15°C for 24 h) averted lethal hypothermia of mice lacking HDAC3 in BAT (HDAC3 BAT KO) exposed to 4°C. STEMCT restored the induction of the thermogenic coactivator PGC-1α along with UCP1 at 22°C, which is greatly impaired in HDAC3-deficient BAT, and deletion of either UCP1 or PGC-1α prevented the protective effect of STEMCT. Remarkably, this protection lasted for up to 7 days. Transcriptional activator C/EBPβ was induced by short-term cold exposure in mouse and human BAT and, uniquely, remained high for 7 days following STEMCT. Adeno-associated virus-mediated knockdown of BAT C/EBPβ in HDAC3 BAT KO mice erased the persistent memory of STEMCT, revealing the existence of a C/EBPβ-dependent and HDAC3-independent cold-adaptive epigenomic memory.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38918428,

title = {Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity},

author = {Bam D Paneru and Julia Chini and Sam J McCright and Nicole DeMarco and Jessica Miller and Leonel D Joannas and Jorge Henao-Mejia and Paul M Titchenell and David M Merrick and Hee-Woong Lim and Mitchell A Lazar and David A Hill},

doi = {10.1038/s41467-024-49632-z},

issn = {2041-1723},

year  = {2024},

date = {2024-06-01},

journal = {Nat Commun},

volume = {15},

number = {1},

pages = {5394},

abstract = {Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38622413,

title = {Nuclear receptor corepressors non-canonically drive glucocorticoid receptor-dependent activation of hepatic gluconeogenesis},

author = {Amy K Hauck and Rashid Mehmood and Bryce J Carpenter and Maxwell T Frankfurter and Michael C Tackenberg and Shin-Ichi Inoue and Maria K Krieg and Fathima N Cassim Bawa and Mohit K Midha and Delaine M Zundell and Kirill Batmanov and Mitchell A Lazar},

doi = {10.1038/s42255-024-01029-4},

issn = {2522-5812},

year  = {2024},

date = {2024-04-01},

journal = {Nat Metab},

abstract = {Nuclear receptor corepressors (NCoRs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3) to alter transcriptional output primarily through repressive chromatin remodelling at target loci. In the liver, loss of HDAC3 causes a marked hepatosteatosis largely because of de-repression of genes involved in lipid metabolism; however, the individual roles and contribution of other complex members to hepatic and systemic metabolic regulation are unclear. Here we show that adult loss of both NCoR1 and NCoR2 (double knockout (KO)) in hepatocytes phenocopied the hepatomegalic fatty liver phenotype of HDAC3 KO. In addition, double KO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCoRs or HDAC3, resulting in profound fasting hypoglycaemia. This surprising HDAC3-independent activation function of NCoR1 and NCoR2 is due to an unexpected loss of chromatin accessibility on deletion of NCoRs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCoRs that is required for metabolic health.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38142970,

title = {Hindbrain REV-ERB nuclear receptors regulate sensitivity to diet-induced obesity and brown adipose tissue pathophysiology},

author = {Lauren N Woodie and Lily C Melink and Ahren J Alberto and Michelle Burrows and Samantha M Fortin and Calvin C Chan and Matthew R Hayes and Mitchell A Lazar},

doi = {10.1016/j.molmet.2023.101861},

issn = {2212-8778},

year  = {2024},

date = {2024-01-01},

journal = {Mol Metab},

volume = {79},

pages = {101861},

abstract = {OBJECTIVE: The dorsal vagal complex (DVC) of the hindbrain is a major point of integration for central and peripheral signals that regulate a wide variety of metabolic functions to maintain energy balance. The REV-ERB nuclear receptors are important modulators of molecular metabolism, but their role in the DVC has yet to be established.nnMETHODS: Male REV-ERBα/β floxed mice received stereotaxic injections of a Cre expressing virus to the DVC to create the DVC REV-ERBα/β double knockout (DVC RDKO). Control littermates received stereotaxic injections to the DVC of a green fluorescent protein expressing virus. Animals were maintained on a normal chow diet or a 60% high-fat diet to observe the metabolic phenotype arising from DVC RDKO under healthy and metabolically stressed conditions.nnRESULTS: DVC RDKO animals on high-fat diet exhibited increased weight gain compared to control animals maintained on the same diet. Increased weight gain in DVC RDKO animals was associated with decreased basal metabolic rate and dampened signature of brown adipose tissue activity. RDKO decreased gene expression of calcitonin receptor in the DVC and tyrosine hydroxylase in the brown adipose tissue.nnCONCLUSIONS: These results suggest a previously unappreciated role of REV-ERB nuclear receptors in the DVC for maintaining energy balance and metabolic rate potentially through indirect sympathetic outflow to the brown adipose tissue.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38077098,

title = {Hepatic Vagal Afferents Convey Clock-Dependent Signals to Regulate Circadian Food Intake},

author = {Lauren N Woodie and Lily C Melink and Mohit Midha and Alan M de Araújo and Caroline E Geisler and Ahren J Alberto and Brianna M Krusen and Delaine M Zundell and Guillaume de Lartigue and Matthew R Hayes and Mitchell A Lazar},

doi = {10.1101/2023.11.30.568080},

year  = {2023},

date = {2023-12-01},

urldate = {2023-12-01},

journal = {bioRxiv},

abstract = {Circadian desynchrony induced by shiftwork or jetlag is detrimental to metabolic health, but how synchronous/desynchronous signals are transmitted among tissues is unknown. Here we report that liver molecular clock dysfunction is signaled to the brain via the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a previously unrecognized homeostatic feedback signal that relies on synchrony between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a therapeutic target for obesity in the setting of chrono-disruption.nnONE SENTENCE SUMMARY: The hepatic vagal afferent nerve signals internal circadian desynchrony between the brain and liver to induce maladaptive food intake patterns.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37952007,

title = {Cardiomyocyte-specific disruption of the circadian BMAL1-REV-ERBα/β regulatory network impacts distinct miRNA species in the murine heart},

author = {Mary N Latimer and Lamario J Williams and Gobinath Shanmugan and Bryce J Carpenter and Mitchell A Lazar and Pieterjan Dierickx and Martin E Young},

doi = {10.1038/s42003-023-05537-z},

issn = {2399-3642},

year  = {2023},

date = {2023-11-01},

journal = {Commun Biol},

volume = {6},

number = {1},

pages = {1149},

abstract = {Circadian disruption increases cardiovascular disease (CVD) risk, through poorly understood mechanisms. Given that small RNA species are critical modulators of cardiac physiology/pathology, we sought to determine the extent to which cardiomyocyte circadian clock (CCC) disruption impacts cardiac small RNA species. Accordingly, we collected hearts from cardiomyocyte-specific Bmal1 knockout (CBK; a model of CCC disruption) and littermate control (CON) mice at multiple times of the day, followed by small RNA-seq. The data reveal 47 differentially expressed miRNAs species in CBK hearts. Subsequent bioinformatic analyses predict that differentially expressed miRNA species in CBK hearts influence processes such as circadian rhythmicity, cellular signaling, and metabolism. Of the induced miRNAs in CBK hearts, 7 are predicted to be targeted by the transcriptional repressors REV-ERBα/β (integral circadian clock components that are directly regulated by BMAL1). Similar to CBK hearts, cardiomyocyte-specific Rev-erbα/β double knockout (CM-RevDKO) mouse hearts exhibit increased let-7c-1-3p, miR-23b-5p, miR-139-3p, miR-5123, and miR-7068-3p levels. Importantly, 19 putative targets of these 5 miRNAs are commonly repressed in CBK and CM-RevDKO heart (of which 16 are targeted by let-7c-1-3p). These observations suggest that disruption of the circadian BMAL1-REV-ERBα/β regulatory network in the heart induces distinct miRNAs, whose mRNA targets impact critical cellular functions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37802023,

title = {An intrinsically disordered region controlling condensation of a circadian clock component and rhythmic transcription in the liver},

author = {Kun Zhu and Isaac J Celwyn and Dongyin Guan and Yang Xiao and Xiang Wang and Wenxiang Hu and Chunjie Jiang and Lan Cheng and Rafael Casellas and Mitchell A Lazar},

doi = {10.1016/j.molcel.2023.09.010},

issn = {1097-4164},

year  = {2023},

date = {2023-10-01},

journal = {Mol Cell},

volume = {83},

number = {19},

pages = {3457--3469.e7},

abstract = {Circadian gene transcription is fundamental to metabolic physiology. Here we report that the nuclear receptor REV-ERBα, a repressive component of the molecular clock, forms circadian condensates in the nuclei of mouse liver. These condensates are dictated by an intrinsically disordered region (IDR) located in the protein's hinge region which specifically concentrates nuclear receptor corepressor 1 (NCOR1) at the genome. IDR deletion diminishes the recruitment of NCOR1 and disrupts rhythmic gene transcription in vivo. REV-ERBα condensates are located at high-order transcriptional repressive hubs in the liver genome that are highly correlated with circadian gene repression. Deletion of the IDR disrupts transcriptional repressive hubs and diminishes silencing of target genes by REV-ERBα. This work demonstrates physiological circadian protein condensates containing REV-ERBα whose IDR is required for hub formation and the control of rhythmic gene expression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37791313,

title = {Novel Roles for the Transcriptional Repressor E4BP4 in Both Cardiac Physiology and Pathophysiology},

author = {Sobuj Mia and Ravi Sonkar and Lamario Williams and Mary N Latimer and David R Rawnsley and Samir Rana and Jin He and Pieterjan Dierickx and Teayoun Kim and Min Xie and Kirk M Habegger and Masato Kubo and Lufang Zhou and Morten B Thomsen and Sumanth D Prabhu and Stuart J Frank and Paul S Brookes and Mitchell A Lazar and Abhinav Diwan and Martin E Young},

doi = {10.1016/j.jacbts.2023.03.016},

issn = {2452-302X},

year  = {2023},

date = {2023-09-01},

journal = {JACC Basic Transl Sci},

volume = {8},

number = {9},

pages = {1141--1156},

abstract = {Circadian clocks temporally orchestrate biological processes critical for cellular/organ function. For example, the cardiomyocyte circadian clock modulates cardiac metabolism, signaling, and electrophysiology over the course of the day, such that, disruption of the clock leads to age-onset cardiomyopathy (through unknown mechanisms). Here, we report that genetic disruption of the cardiomyocyte clock results in chronic induction of the transcriptional repressor E4BP4. Importantly, E4BP4 deletion prevents age-onset cardiomyopathy following clock disruption. These studies also indicate that E4BP4 regulates both cardiac metabolism (eg, fatty acid oxidation) and electrophysiology (eg, QT interval). Collectively, these studies reveal that E4BP4 is a novel regulator of both cardiac physiology and pathophysiology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37626048,

title = {Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice},

author = {Jiyeon Lee and Julie M Dimitry and Jong Hee Song and Minsoo Son and Patrick W Sheehan and Melvin W King and G Travis Tabor and Young Ah Goo and Mitchell A Lazar and Leonard Petrucelli and Erik S Musiek},

doi = {10.1038/s41467-023-40927-1},

issn = {2041-1723},

year  = {2023},

date = {2023-08-01},

journal = {Nat Commun},

volume = {14},

number = {1},

pages = {5197},

abstract = {Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36927960,

title = {RIP140 deficiency enhances cardiac fuel metabolism and protects mice from heart failure},

author = {Tsunehisa Yamamoto and Santosh K Maurya and Elizabeth Pruzinsky and Kirill Batmanov and Yang Xiao and Sarah M Sulon and Tomoya Sakamoto and Yang Wang and Ling Lai and Kendra S McDaid and Swapnil V Shewale and Teresa C Leone and Timothy R Koves and Deborah M Muoio and Pieterjan Dierickx and Mitchell A Lazar and E Douglas Lewandowski and Daniel P Kelly},

doi = {10.1172/JCI162309},

issn = {1558-8238},

year  = {2023},

date = {2023-05-01},

journal = {J Clin Invest},

volume = {133},

number = {9},

abstract = {During the development of heart failure (HF), the capacity for cardiomyocyte (CM) fatty acid oxidation (FAO) and ATP production is progressively diminished, contributing to pathologic cardiac hypertrophy and contractile dysfunction. Receptor-interacting protein 140 (RIP140, encoded by Nrip1) has been shown to function as a transcriptional corepressor of oxidative metabolism. We found that mice with striated muscle deficiency of RIP140 (strNrip1-/-) exhibited increased expression of a broad array of genes involved in mitochondrial energy metabolism and contractile function in heart and skeletal muscle. strNrip1-/- mice were resistant to the development of pressure overload-induced cardiac hypertrophy, and CM-specific RIP140-deficient (csNrip1-/-) mice were protected against the development of HF caused by pressure overload combined with myocardial infarction. Genomic enhancers activated by RIP140 deficiency in CMs were enriched in binding motifs for transcriptional regulators of mitochondrial function (estrogen-related receptor) and cardiac contractile proteins (myocyte enhancer factor 2). Consistent with a role in the control of cardiac fatty acid oxidation, loss of RIP140 in heart resulted in augmented triacylglyceride turnover and fatty acid utilization. We conclude that RIP140 functions as a suppressor of a transcriptional regulatory network that controls cardiac fuel metabolism and contractile function, representing a potential therapeutic target for the treatment of HF.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37149727,

title = {The REV-ERB Nuclear Receptors: Timekeepers for the Core Clock Period and Metabolism},

author = {Marine Adlanmerini and Mitchell A Lazar},

doi = {10.1210/endocr/bqad069},

issn = {1945-7170},

year  = {2023},

date = {2023-04-01},

journal = {Endocrinology},

volume = {164},

number = {6},

abstract = {REV-ERB nuclear receptors are potent transcriptional repressors that play an important role in the core mammalian molecular clock and metabolism. Deletion of both REV-ERBα and its largely redundant isoform REV-ERBβ in a murine tissue-specific manner have shed light on their specific functions in clock mechanisms and circadian metabolism. This review highlights recent findings that establish REV-ERBs as crucial circadian timekeepers in a variety of tissues, regulating overlapping and distinct processes that maintain normal physiology and protect from metabolic dysfunction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37066875,

title = {Hepatocyte SREBP signaling mediates clock communication within the liver},

author = {Dongyin Guan and Hosung Bae and Dishu Zhou and Ying Chen and Chunjie Jiang and Cam Mong La and Yang Xiao and Kun Zhu and Wenxiang Hu and Trang Minh Trinh and Panpan Liu and Ying Xiong and Bishuang Cai and Cholsoon Jang and Mitchell A Lazar},

doi = {10.1172/JCI163018},

issn = {1558-8238},

year  = {2023},

date = {2023-04-01},

journal = {J Clin Invest},

volume = {133},

number = {8},

abstract = {Rhythmic intraorgan communication coordinates environmental signals and the cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific KO of core components of the molecular clock Rev-erbα and -β (Reverb-hDKO) alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in nonparenchymal cells (NPCs) of the liver. Here, we report that in fatty liver caused by diet-induced obesity (DIO), hepatocyte SREBP cleavage-activating protein (SCAP) was required for Reverb-hDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in liver macrophages (LMs). Integrative analyses of isolated hepatocytes and LMs revealed that SCAP-dependent lipidomic changes in REV-ERB-depleted hepatocytes led to the enhancement of LM metabolic rhythms. Hepatocytic loss of REV-ERBα and β (REV-ERBs) also attenuated LM rhythms via SCAP-independent polypeptide secretion. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in fatty liver disease caused by DIO.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36753562,

title = {Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis},

author = {Yang Xiao and Kirill Batmanov and Wenxiang Hu and Kun Zhu and Alexander Y Tom and Dongyin Guan and Chunjie Jiang and Lan Cheng and Sam J McCright and Eric C Yang and Matthew R Lanza and Yifan Liu and David A Hill and Mitchell A Lazar},

doi = {10.1126/scitranslmed.adc9653},

issn = {1946-6242},

year  = {2023},

date = {2023-02-01},

journal = {Sci Transl Med},

volume = {15},

number = {682},

pages = {eadc9653},

abstract = {Current therapeutic strategies for treating nonalcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mice and humans. At the nonalcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which were mainly demarcated by receptor tyrosine kinase ephrin type B receptor 2 (EphB2). EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomous inflammation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in a mouse model of NASH. Thus, EphB2-expressing hepatocytes contribute to NASH progression and may serve as a potential therapeutic target.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37061999,

title = {Genes and my development},

author = {Mitchell A Lazar},

doi = {10.1101/gad.350369.122},

issn = {1549-5477},

year  = {2023},

date = {2023-01-01},

journal = {Genes Dev},

volume = {37},

number = {1-2},

pages = {35--36},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36071283,

title = {Modelling metabolic diseases and drug response using stem cells and organoids},

author = {Wenxiang Hu and Mitchell A Lazar},

doi = {10.1038/s41574-022-00733-z},

issn = {1759-5037},

year  = {2022},

date = {2022-12-01},

journal = {Nat Rev Endocrinol},

volume = {18},

number = {12},

pages = {744--759},

abstract = {Metabolic diseases, including obesity, diabetes mellitus and cardiovascular disease, are a major threat to health in the modern world, but efforts to understand the underlying mechanisms and develop rational treatments are limited by the lack of appropriate human model systems. Notably, advances in stem cell and organoid technology allow the generation of cellular models that replicate the histological, molecular and physiological properties of human organs. Combined with marked improvements in gene editing tools, human stem cells and organoids provide unprecedented systems for studying mechanisms of metabolic diseases. Here, we review progress made over the past decade in the generation and use of stem cell-derived metabolic cell types and organoids in metabolic disease research, especially obesity and liver diseases. In particular, we discuss the limitations of animal models and the advantages of stem cells and organoids, including their application to metabolic diseases. We also discuss mechanisms of drug action, understanding the efficacy and toxicity of existing therapies, screening for new treatments and pursuing personalized therapies. We highlight the potential of combining stem cell-derived organoids with gene editing and functional genomics to revolutionize the approach to finding treatments for metabolic diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36250463,

title = {Tugs-of-war in science},

author = {Mitchell A Lazar},

doi = {10.1172/JCI165312},

issn = {1558-8238},

year  = {2022},

date = {2022-10-01},

journal = {J Clin Invest},

volume = {132},

number = {20},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36179011,

title = {T in visceral adipose tissue up-regulate circadian-clock expression to promote fitness and enforce a diurnal rhythm of lipolysis},

author = {Tianli Xiao and P Kent Langston and Andrés R Muñoz-Rojas and Teshika Jayewickreme and Mitchell A Lazar and Christophe Benoist and Diane Mathis},

doi = {10.1126/sciimmunol.abl7641},

issn = {2470-9468},

year  = {2022},

date = {2022-09-01},

journal = {Sci Immunol},

volume = {7},

number = {75},

pages = {eabl7641},

abstract = {Regulatory T cells (T) in nonlymphoid organs provide critical brakes on inflammation and regulate tissue homeostasis. Although so-called "tissue T" are phenotypically and functionally diverse, serving to optimize their performance and survival, up-regulation of pathways related to circadian rhythms is a feature they share. Yet the diurnal regulation of T and its consequences are controversial and poorly understood. Here, we profiled diurnal variations in visceral adipose tissue (VAT) and splenic T in the presence and absence of core-clock genes. VAT, but not splenic, T up-regulated their cell-intrinsic circadian program and exhibited diurnal variations in their activation and metabolic state. BMAL1 deficiency specifically in T led to constitutive activation and poor oxidative metabolism in VAT, but not splenic, T. Disruption of core-clock components resulted in loss of fitness: BMAL1-deficient VAT T were preferentially lost during competitive transfers and in heterozygous T females. After 16 weeks of high-fat diet feeding, VAT inflammation was increased in mice harboring BMAL1-deficient T, and the remaining cells lost the transcriptomic signature of bona fide VAT T. Unexpectedly, VAT T suppressed adipocyte lipolysis, and BMAL1 deficiency specifically in T abrogated the characteristic diurnal variation in adipose tissue lipolysis, resulting in enhanced suppression of lipolysis throughout the day. These findings argue for the importance of the cell-intrinsic clock program in optimizing VAT T function and fitness.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35939699,

title = {Balanced control of thermogenesis by nuclear receptor corepressors in brown adipose tissue},

author = {Hannah J Richter and Amy K Hauck and Kirill Batmanov and Shin-Ichi Inoue and Bethany N So and Mindy Kim and Matthew J Emmett and Ronald N Cohen and Mitchell A Lazar},

doi = {10.1073/pnas.2205276119},

issn = {1091-6490},

year  = {2022},

date = {2022-08-01},

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

volume = {119},

number = {33},

pages = {e2205276119},

abstract = {Brown adipose tissue (BAT) is a key thermogenic organ whose expression of uncoupling protein 1 (UCP1) and ability to maintain body temperature in response to acute cold exposure require histone deacetylase 3 (HDAC3). HDAC3 exists in tight association with nuclear receptor corepressors (NCoRs) NCoR1 and NCoR2 (also known as silencing mediator of retinoid and thyroid receptors [SMRT]), but the functions of NCoR1/2 in BAT have not been established. Here we report that as expected, genetic loss of NCoR1/2 in BAT (NCoR1/2 BAT-dKO) leads to loss of HDAC3 activity. In addition, HDAC3 is no longer bound at its physiological genomic sites in the absence of NCoR1/2, leading to a shared deregulation of BAT lipid metabolism between NCoR1/2 BAT-dKO and HDAC3 BAT-KO mice. Despite these commonalities, loss of NCoR1/2 in BAT does not phenocopy the cold sensitivity observed in HDAC3 BAT-KO, nor does loss of either corepressor alone. Instead, BAT lacking NCoR1/2 is inflamed, particularly with respect to the interleukin-17 axis that increases thermogenic capacity by enhancing innervation. Integration of BAT RNA sequencing and chromatin immunoprecipitation sequencing data revealed that NCoR1/2 directly regulate , which integrates extracellular matrix remodeling and inflammation. These findings reveal pleiotropic functions of the NCoR/HDAC3 corepressor complex in BAT, such that HDAC3-independent suppression of BAT inflammation counterbalances stimulation of HDAC3 activity in the control of thermogenesis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35956312,

title = {The Circadian Regulation of Nutrient Metabolism in Diet-Induced Obesity and Metabolic Disease},

author = {Lauren N Woodie and Kaan T Oral and Brianna M Krusen and Mitchell A Lazar},

doi = {10.3390/nu14153136},

issn = {2072-6643},

year  = {2022},

date = {2022-07-01},

journal = {Nutrients},

volume = {14},

number = {15},

abstract = {Obesity and other metabolic diseases are major public health issues that are particularly prevalent in industrialized societies where circadian rhythmicity is disturbed by shift work, jet lag, and/or social obligations. In mammals, daylight entrains the hypothalamic suprachiasmatic nucleus (SCN) to a ≈24 h cycle by initiating a transcription/translation feedback loop (TTFL) of molecular clock genes. The downstream impacts of the TTFL on clock-controlled genes allow the SCN to set the rhythm for the majority of physiological, metabolic, and behavioral processes. The TTFL, however, is ubiquitous and oscillates in tissues throughout the body. Tissues outside of the SCN are entrained to other signals, such as fed/fasting state, rather than light input. This system requires a considerable amount of biological flexibility as it functions to maintain homeostasis across varying conditions contained within a 24 h day. In the face of either circadian disruption (e.g., jet lag and shift work) or an obesity-induced decrease in metabolic flexibility, this finely tuned mechanism breaks down. Indeed, both human and rodent studies have found that obesity and metabolic disease develop when endogenous circadian pacing is at odds with the external cues. In the following review, we will delve into what is known on the circadian rhythmicity of nutrient metabolism and discuss obesity as a circadian disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35663017,

title = {Global-run on sequencing identifies  as an Akt-dependent long noncoding RNA involved in insulin sensitivity},

author = {Dominic Santoleri and Hee-Woong Lim and Matthew J Emmett and Julian Stoute and Matthew J Gavin and Jaimarie Sostre-Colón and Kahealani Uehara and Jaclyn E Welles and Kathy Fange Liu and Mitchell A Lazar and Paul M Titchenell},

doi = {10.1016/j.isci.2022.104410},

issn = {2589-0042},

year  = {2022},

date = {2022-06-01},

journal = {iScience},

volume = {25},

number = {6},

pages = {104410},

abstract = {The insulin responsive Akt and FoxO1 signaling axis is a key regulator of the hepatic transcriptional response to nutrient intake. Here, we used global run-on sequencing (GRO-seq) to measure the nascent transcriptional response to fasting and refeeding as well as define the specific role of hepatic Akt and FoxO1 signaling in mediating this response. We identified 599 feeding-regulated transcripts, as well as over 6,000 eRNAs, and mapped their dependency on Akt and FoxO1 signaling. Further, we identified several feeding-regulated lncRNAs, including the lncRNA , whose expression was dependent upon the liver Akt-FoxO1 axis. Restoring  expression in mice lacking liver Akt improved insulin sensitivity and induced glucokinase protein expression, indicating that Akt-dependent control of  contributes to the translational control of glucokinase. More broadly, we have generated a unique genome-wide dataset that defines the feeding and Akt/FoxO1-dependent transcriptional changes in response to nutrient availability.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35394046,

title = {Phosphorylated MED1 links transcription recycling and cancer growth},

author = {Zhong Chen and Zhenqing Ye and Raymond E Soccio and Tomoyoshi Nakadai and William Hankey and Yue Zhao and Furong Huang and Fuwen Yuan and Hongyan Wang and Zhifen Cui and Benjamin Sunkel and Dayong Wu and Richard K Dzeng and Jennifer M Thomas-Ahner and Tim H M Huang and Steven K Clinton and Jiaoti Huang and Mitchell A Lazar and Victor X Jin and Robert G Roeder and Qianben Wang},

doi = {10.1093/nar/gkac246},

issn = {1362-4962},

year  = {2022},

date = {2022-05-01},

journal = {Nucleic Acids Res},

volume = {50},

number = {8},

pages = {4450--4463},

abstract = {Mediator activates RNA polymerase II (Pol II) function during transcription, but it remains unclear whether Mediator is able to travel with Pol II and regulate Pol II transcription beyond the initiation and early elongation steps. By using in vitro and in vivo transcription recycling assays, we find that human Mediator 1 (MED1), when phosphorylated at the mammal-specific threonine 1032 by cyclin-dependent kinase 9 (CDK9), dynamically moves along with Pol II throughout the transcribed genes to drive Pol II recycling after the initial round of transcription. Mechanistically, MED31 mediates the recycling of phosphorylated MED1 and Pol II, enhancing mRNA output during the transcription recycling process. Importantly, MED1 phosphorylation increases during prostate cancer progression to the lethal phase, and pharmacological inhibition of CDK9 decreases prostate tumor growth by decreasing MED1 phosphorylation and Pol II recycling. Our results reveal a novel role of MED1 in Pol II transcription and identify phosphorylated MED1 as a targetable driver of dysregulated Pol II recycling in cancer.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35263797,

title = {Circadian Regulation of Gene Expression and Metabolism in the Liver},

author = {Dongyin Guan and Mitchell A Lazar},

doi = {10.1055/a-1792-4240},

issn = {1098-8971},

year  = {2022},

date = {2022-05-01},

journal = {Semin Liver Dis},

volume = {42},

number = {2},

pages = {113--121},

abstract = {Circadian rhythms are approximately 24-hour cycles of variation in physiological processes, gene expression, and behavior. They result from the interplay of internal biological clocks with daily environmental rhythms, including light/dark and feeding/fasting. Note that 24-hour rhythms of liver metabolic processes have been known for almost 100 years. Modern studies reveal that, like metabolism, hepatic gene expression is highly rhythmic. Genetic or environmental changes can disrupt the circadian rhythms of the liver, leading to metabolic disorders and hepatocellular carcinoma. In this review, we summarize the current understanding of mechanisms regulating rhythmic gene expression in the liver, highlighting the roles of transcription factors that comprise the core clock molecular as well as noncanonical regulators. We emphasize the plasticity of circadian rhythms in the liver as it responds to multiple inputs from the external and internal environments as well as the potential of circadian medicine to impact liver-related diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35273075,

title = {Isoform-specific functions of PPARγ in gene regulation and metabolism},

author = {Wenxiang Hu and Chunjie Jiang and Mindy Kim and Yang Xiao and Hannah J Richter and Dongyin Guan and Kun Zhu and Brianna M Krusen and Arielle N Roberts and Jessica Miller and David J Steger and Mitchell A Lazar},

doi = {10.1101/gad.349232.121},

issn = {1549-5477},

year  = {2022},

date = {2022-03-01},

journal = {Genes Dev},

volume = {36},

number = {5-6},

pages = {300--312},

abstract = {Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPARγ by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPARγ isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. Strikingly, although PPARγ1 and PPARγ2 contain identical DNA binding domains, we uncovered isoform-specific genomic binding sites in addition to shared sites. Moreover, PPARγ1 and PPARγ2 regulated a different set of genes in adipose tissue depots, suggesting distinct roles in adipocyte biology. Indeed, mice with selective deficiency of PPARγ1 maintained body temperature better than wild-type or PPARγ2-deficient mice. Most remarkably, although TZD treatment improved glucose tolerance in mice lacking either PPARγ1 or PPARγ2, the PPARγ1-deficient mice were protected from TZD-induced body weight gain compared with PPARγ2-deficient mice. Thus, PPARγ isoforms have specific and separable metabolic functions that may be targeted to improve therapy for insulin resistance and diabetes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35036997,

title = {Circadian REV-ERBs repress  to activate NAMPT-dependent NAD biosynthesis and sustain cardiac function},

author = {Pieterjan Dierickx and Kun Zhu and Bryce J Carpenter and Chunjie Jiang and Marit W Vermunt and Yang Xiao and Timothy S Luongo and Tsunehisa Yamamoto and Íngrid Martí-Pàmies and Sobuj Mia and Mary Latimer and Abhinav Diwan and Juanjuan Zhao and Amy K Hauck and Brianna Krusen and Hoang C B Nguyen and Gerd A Blobel and Daniel P Kelly and Liming Pei and Joseph A Baur and Martin E Young and Mitchell A Lazar},

doi = {10.1038/s44161-021-00001-9},

issn = {2731-0590},

year  = {2022},

date = {2022-01-01},

journal = {Nat Cardiovasc Res},

volume = {1},

number = {1},

pages = {45--58},

abstract = {The heart is a highly metabolic organ that uses multiple energy sources to meet its demand for ATP production. Diurnal feeding-fasting cycles result in substrate availability fluctuations which, together with increased energetic demand during the active period, impose a need for rhythmic cardiac metabolism. The nuclear receptors REV-ERBα and β are essential repressive components of the molecular circadian clock and major regulators of metabolism. To investigate their role in the heart, here we generated mice with cardiomyocyte (CM)-specific deletion of both s, which died prematurely due to dilated cardiomyopathy. Loss of  markedly downregulated fatty acid oxidation genes prior to overt pathology, which was mediated by induction of the transcriptional repressor E4BP4, a direct target of cardiac REV-ERBs. E4BP4 directly controls circadian expression of  and its biosynthetic product NAD via distal -regulatory elements. Thus, REV-ERB-mediated E4BP4 repression is required for  expression and NAD production by the salvage pathway. Together, these results highlight the indispensable role of circadian REV-ERBs in cardiac gene expression, metabolic homeostasis and function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37389009,

title = {Nicotinamide Riboside Improves Cardiac Function and Prolongs Survival After Disruption of the Cardiomyocyte Clock},

author = {Pieterjan Dierickx and Bryce J Carpenter and Isaac Celwyn and Daniel P Kelly and Joseph A Baur and Mitchell A Lazar},

doi = {10.3389/fmmed.2022.887733},

issn = {2674-0095},

year  = {2022},

date = {2022-01-01},

journal = {Front Mol Med},

volume = {2},

abstract = {The REV-ERB nuclear receptors are key components of the circadian clock. Loss of REV-ERBs in the mouse heart causes dilated cardiomyopathy and premature lethality. This is associated with a marked reduction in NAD production, but whether this plays a role in the pathophysiology of this heart failure model is not known. Here, we show that supplementation with the NAD precursor NR as a dietary supplement improves heart function and extends the lifespan of female mice lacking cardiac REV-ERBs. Thus, boosting NAD levels can improve cardiac function in a setting of heart failure caused by disruption of circadian clock factors, providing new insights into the links between the circadian clock, energy metabolism, and cardiac function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34705514,

title = {REV-ERB nuclear receptors in the suprachiasmatic nucleus control circadian period and restrict diet-induced obesity},

author = {Marine Adlanmerini and Brianna M Krusen and Hoang C B Nguyen and Clare W Teng and Lauren N Woodie and Michael C Tackenberg and Caroline E Geisler and Jane Gaisinsky and Lindsey C Peed and Bryce J Carpenter and Matthew R Hayes and Mitchell A Lazar},

doi = {10.1126/sciadv.abh2007},

issn = {2375-2548},

year  = {2021},

date = {2021-10-01},

journal = {Sci Adv},

volume = {7},

number = {44},

pages = {eabh2007},

abstract = {Circadian disruption, as occurs in shift work, is associated with metabolic diseases often attributed to a discordance between internal clocks and environmental timekeepers. REV-ERB nuclear receptors are key components of the molecular clock, but their specific role in the SCN master clock is unknown. We report here that mice lacking circadian REV-ERB nuclear receptors in the SCN maintain free-running locomotor and metabolic rhythms, but these rhythms are notably shortened by 3 hours. When housed under a 24-hour light:dark cycle and fed an obesogenic diet, these mice gained excess weight and accrued more liver fat than controls. These metabolic disturbances were corrected by matching environmental lighting to the shortened endogenous 21-hour clock period, which decreased food consumption. Thus, SCN REV-ERBs are not required for rhythmicity but determine the free-running period length. Moreover, these results support the concept that dissonance between environmental conditions and endogenous time periods causes metabolic disruption.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34338232,

title = {Interconnections between circadian clocks and metabolism},

author = {Dongyin Guan and Mitchell A Lazar},

doi = {10.1172/JCI148278},

issn = {1558-8238},

year  = {2021},

date = {2021-08-01},

journal = {J Clin Invest},

volume = {131},

number = {15},

abstract = {Circadian rhythms evolved through adaptation to daily light/dark changes in the environment; they are believed to be regulated by the core circadian clock interlocking feedback loop. Recent studies indicate that each core component executes general and specific functions in metabolism. Here, we review the current understanding of the role of these core circadian clock genes in the regulation of metabolism using various genetically modified animal models. Additionally, emerging evidence shows that exposure to environmental stimuli, such as artificial light, unbalanced diet, mistimed eating, and exercise, remodels the circadian physiological processes and causes metabolic disorders. This Review summarizes the reciprocal regulation between the circadian clock and metabolism, highlights remaining gaps in knowledge about the regulation of circadian rhythms and metabolism, and examines potential applications to human health and disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34233159,

title = {Individual-specific functional epigenomics reveals genetic determinants of adverse metabolic effects of glucocorticoids},

author = {Wenxiang Hu and Chunjie Jiang and Mindy Kim and Wenjian Yang and Kun Zhu and Dongyin Guan and Wenjian Lv and Yang Xiao and Jessica R Wilson and Daniel J Rader and Ching-Hon Pui and Mary V Relling and Mitchell A Lazar},

doi = {10.1016/j.cmet.2021.06.004},

issn = {1932-7420},

year  = {2021},

date = {2021-08-01},

journal = {Cell Metab},

volume = {33},

number = {8},

pages = {1592--1609.e7},

abstract = {Glucocorticoids (GCs) are widely used as anti-inflammatory drugs, but their long-term use has severe metabolic side effects. Here, by treating multiple individual adipose stem cell-derived adipocytes and induced pluripotent stem cell-derived hepatocytes with the potent GC dexamethasone (Dex), we uncovered cell-type-specific and individual-specific GC-dependent transcriptomes and glucocorticoid receptor (GR) cistromes. Individual-specific GR binding could be traced to single-nucleotide polymorphisms (SNPs) that altered the binding motifs of GR or its cooperating factors. We also discovered another set of genetic variants that modulated Dex response through affecting chromatin accessibility or chromatin architecture. Several SNPs that altered Dex-regulated GR binding and gene expression controlled Dex-driven metabolic perturbations. Remarkably, these genetic variations were highly associated with increases in serum glucose, lipids, and body mass in subjects on GC therapy. Knowledge of the genetic variants that predispose individuals to metabolic side effects allows for a precision medicine approach to the use of clinically relevant GCs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33220489,

title = {Nuclear receptors and transcriptional regulation in non-alcoholic fatty liver disease},

author = {Yang Xiao and Mindy Kim and Mitchell A Lazar},

doi = {10.1016/j.molmet.2020.101119},

issn = {2212-8778},

year  = {2021},

date = {2021-08-01},

journal = {Mol Metab},

volume = {50},

pages = {101119},

abstract = {BACKGROUND: As a result of a sedentary lifestyle and excess food consumption in modern society, non-alcoholic fatty liver disease (NAFLD) characterized by fat accumulation in the liver is becoming a major disease burden. Non-alcoholic steatohepatitis (NASH) is an advanced form of NAFLD characterized by inflammation and fibrosis that can lead to hepatocellular carcinoma and liver failure. Nuclear receptors (NRs) are a family of ligand-regulated transcription factors that closely control multiple aspects of metabolism. Their transcriptional activity is modulated by various ligands, including hormones and lipids. NRs serve as potential pharmacological targets for NAFLD/NASH and other metabolic diseases.nnSCOPE OF REVIEW: In this review, we provide a comprehensive overview of NRs that have been studied in the context of NAFLD/NASH with a focus on their transcriptional regulation, function in preclinical models, and studies of their clinical utility.nnMAJOR CONCLUSIONS: The transcriptional regulation of NRs is context-dependent. During the dynamic progression of NAFLD/NASH, NRs play diverse roles in multiple organs and different cell types in the liver, which highlights the necessity of targeting NRs in a stage-specific and cell-type-specific manner to enhance the efficacy and safety of treatment methods.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33602873,

title = {A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver},

author = {Yehuda Shabtai and Nagaswaroop K Nagaraj and Kirill Batmanov and Young-Wook Cho and Yuxia Guan and Chunjie Jiang and Jarrett Remsberg and Douglas Forrest and Mitchell A Lazar},

doi = {10.1101/gad.345686.120},

issn = {1549-5477},

year  = {2021},

date = {2021-03-01},

journal = {Genes Dev},

volume = {35},

number = {5-6},

pages = {367--378},

abstract = {Thyroid hormones (THs) are powerful regulators of metabolism with major effects on body weight, cholesterol, and liver fat that have been exploited pharmacologically for many years. Activation of gene expression by TH action is canonically ascribed to a hormone-dependent "switch" from corepressor to activator binding to thyroid hormone receptors (TRs), while the mechanism of TH-dependent repression is controversial. To address this, we generated a mouse line in which endogenous TRβ1 was epitope-tagged to allow precise chromatin immunoprecipitation at the low physiological levels of TR and defined high-confidence binding sites where TRs functioned at enhancers regulated in the same direction as the nearest gene in a TRβ-dependent manner. Remarkably, although positive and negative regulation by THs have been ascribed to different mechanisms, TR binding was highly enriched at canonical DR4 motifs irrespective of the transcriptional direction of the enhancer. The canonical NCoR1/HDAC3 corepressor complex was reduced but not completely dismissed by TH and, surprisingly, similar effects were seen at enhancers associated with negatively as well as positively regulated genes. Conversely, coactivator CBP was found at all TH-regulated enhancers, with transcriptional activity correlating with the ratio of CBP to NCoR rather than their presence or absence. These results demonstrate that, in contrast to the canonical "all or none" coregulator switch model, THs regulate gene expression by orchestrating a shift in the relative binding of corepressors and coactivators.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34093224,

title = {Liver Transcriptome Dynamics During Hibernation Are Shaped by a Shifting Balance Between Transcription and RNA Stability},

author = {Austin E Gillen and Rui Fu and Kent A Riemondy and Jennifer Jager and Bin Fang and Mitchell A Lazar and Sandra L Martin},

doi = {10.3389/fphys.2021.662132},

issn = {1664-042X},

year  = {2021},

date = {2021-01-01},

journal = {Front Physiol},

volume = {12},

pages = {662132},

abstract = {Hibernators dramatically lower metabolism to save energy while fasting for months. Prolonged fasting challenges metabolic homeostasis, yet small-bodied hibernators emerge each spring ready to resume all aspects of active life, including immediate reproduction. The liver is the body's metabolic hub, processing and detoxifying macromolecules to provide essential fuels to brain, muscle and other organs throughout the body. Here we quantify changes in liver gene expression across several distinct physiological states of hibernation in 13-lined ground squirrels, using RNA-seq to measure the steady-state transcriptome and GRO-seq to measure transcription for the first time in a hibernator. Our data capture key timepoints in both the seasonal and torpor-arousal cycles of hibernation. Strong positive correlation between transcription and the transcriptome indicates that transcriptional control dominates the known seasonal reprogramming of metabolic gene expression in liver for hibernation. During the torpor-arousal cycle, however, discordance develops between transcription and the steady-state transcriptome by at least two mechanisms: 1) although not transcribed during torpor, some transcripts are unusually stable across the torpor bout; and 2) unexpectedly, on some genes, our data suggest continuing, slow elongation with a failure to terminate transcription across the torpor bout. While the steady-state RNAs corresponding to these read through transcripts did not increase during torpor, they did increase shortly after rewarming despite their simultaneously low transcription. Both of these mechanisms would assure the immediate availability of functional transcripts upon rewarming. Integration of transcriptional, post-transcriptional and RNA stability control mechanisms, all demonstrated in these data, likely initiate a serial gene expression program across the short euthermic period that restores the tissue and prepares the animal for the next bout of torpor.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33284441,

title = {Using GRO-Seq to Measure Circadian Transcription and Discover Circadian Enhancers},

author = {Bin Fang and Dongyin Guan and Mitchell A Lazar},

doi = {10.1007/978-1-0716-0381-9_10},

issn = {1940-6029},

year  = {2021},

date = {2021-01-01},

journal = {Methods Mol Biol},

volume = {2130},

pages = {127--148},

abstract = {Circadian gene transcription transmits timing information and drives cyclic physiological processes across various tissues. Recent studies indicate that oscillating enhancer activity is a major driving force of rhythmic gene transcription. Functional circadian enhancers can be identified in an unbiased manner by correlation with the rhythms of nearby gene transcription.Global run-on sequencing (GRO-seq) measures nascent transcription of both pre-mRNAs and enhancer RNAs (eRNAs) at a genome-wide level, making it a unique tool for unraveling complex gene regulation mechanisms in vivo. Here, we describe a comprehensive protocol, ranging from wet lab to in silico analysis, for detecting and quantifying circadian transcription of genes and eRNAs. Moreover, using gene-eRNA correlation, we detail the steps necessary to identify functional enhancers and transcription factors (TFs) that control circadian gene expression in vivo. While we use mouse liver as an example, this protocol is applicable for multiple tissues.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33021965,

title = {Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice},

author = {Marine Adlanmerini and Hoang Cb Nguyen and Brianna M Krusen and Clare W Teng and Caroline E Geisler and Lindsey C Peed and Bryce J Carpenter and Matthew R Hayes and Mitchell A Lazar},

doi = {10.1172/JCI140424},

issn = {1558-8238},

year  = {2021},

date = {2021-01-01},

journal = {J Clin Invest},

volume = {131},

number = {1},

abstract = {Obesity occurs when energy expenditure is outweighed by energy intake. Tuberal hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), control food intake and energy expenditure. Here we report that, in contrast with females, male mice lacking circadian nuclear receptors REV-ERBα and -β in the tuberal hypothalamus (HDKO mice) gained excessive weight on an obesogenic high-fat diet due to both decreased energy expenditure and increased food intake during the light phase. Moreover, rebound food intake after fasting was markedly increased in HDKO mice. Integrative transcriptomic and cistromic analyses revealed that such disruption in feeding behavior was due to perturbed REV-ERB-dependent leptin signaling in the ARC. Indeed, in vivo leptin sensitivity was impaired in HDKO mice on an obesogenic diet in a diurnal manner. Thus, REV-ERBs play a crucial role in hypothalamic control of food intake and diurnal leptin sensitivity in diet-induced obesity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32392281,

title = {Transcriptional Control of Circadian Rhythms and Metabolism: A Matter of Time and Space},

author = {Yong Hoon Kim and Mitchell A Lazar},

doi = {10.1210/endrev/bnaa014},

issn = {1945-7189},

year  = {2020},

date = {2020-10-01},

journal = {Endocr Rev},

volume = {41},

number = {5},

pages = {707--732},

abstract = {All biological processes, living organisms, and ecosystems have evolved with the Sun that confers a 24-hour periodicity to life on Earth. Circadian rhythms arose from evolutionary needs to maximize daily organismal fitness by enabling organisms to mount anticipatory and adaptive responses to recurrent light-dark cycles and associated environmental changes. The clock is a conserved feature in nearly all forms of life, ranging from prokaryotes to virtually every cell of multicellular eukaryotes. The mammalian clock comprises transcription factors interlocked in negative feedback loops, which generate circadian expression of genes that coordinate rhythmic physiology. In this review, we highlight previous and recent studies that have advanced our understanding of the transcriptional architecture of the mammalian clock, with a specific focus on epigenetic mechanisms, transcriptomics, and 3-dimensional chromatin architecture. In addition, we discuss reciprocal ways in which the clock and metabolism regulate each other to generate metabolic rhythms. We also highlight implications of circadian biology in human health, ranging from genetic and environment disruptions of the clock to novel therapeutic opportunities for circadian medicine. Finally, we explore remaining fundamental questions and future challenges to advancing the field forward.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32732282,

title = {The hepatocyte clock and feeding control chronophysiology of multiple liver cell types},

author = {Dongyin Guan and Ying Xiong and Trang Minh Trinh and Yang Xiao and Wenxiang Hu and Chunjie Jiang and Pieterjan Dierickx and Cholsoon Jang and Joshua D Rabinowitz and Mitchell A Lazar},

doi = {10.1126/science.aba8984},

issn = {1095-9203},

year  = {2020},

date = {2020-09-01},

journal = {Science},

volume = {369},

number = {6509},

pages = {1388--1394},

abstract = {Most cells of the body contain molecular clocks, but the requirement of peripheral clocks for rhythmicity and their effects on physiology are not well understood. We show that deletion of core clock components REV-ERBα and REV-ERBβ in adult mouse hepatocytes disrupts diurnal rhythms of a subset of liver genes and alters the diurnal rhythm of de novo lipogenesis. Liver function is also influenced by nonhepatocytic cells, and the loss of hepatocyte REV-ERBs remodels the rhythmic transcriptomes and metabolomes of multiple cell types within the liver. Finally, alteration of food availability demonstrates the hierarchy of the cell-intrinsic hepatocyte clock mechanism and the feeding environment. Together, these studies reveal previously unsuspected roles of the hepatocyte clock in the physiological coordination of nutritional signals and cell-cell communication controlling rhythmic metabolism.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32760002,

title = {Dichotomous engagement of HDAC3 activity governs inflammatory responses},

author = {Hoang C B Nguyen and Marine Adlanmerini and Amy K Hauck and Mitchell A Lazar},

doi = {10.1038/s41586-020-2576-2},

issn = {1476-4687},

year  = {2020},

date = {2020-08-01},

journal = {Nature},

volume = {584},

number = {7820},

pages = {286--290},

abstract = {The histone deacetylases (HDACs) are a superfamily of chromatin-modifying enzymes that silence transcription through the modification of histones. Among them, HDAC3 is unique in that interaction with nuclear receptor corepressors 1 and 2 (NCoR1/2) is required to engage its catalytic activity. However, global loss of HDAC3 also results in the repression of transcription, the mechanism of which is currently unclear. Here we report that, during the activation of macrophages by lipopolysaccharides, HDAC3 is recruited to activating transcription factor 2 (ATF2)-bound sites without NCoR1/2 and activates the expression of inflammatory genes through a non-canonical mechanism. By contrast, the deacetylase activity of HDAC3 is selectively engaged at ATF3-bound sites that suppress Toll-like receptor signalling. Loss of HDAC3 in macrophages safeguards mice from lethal exposure to lipopolysaccharides, but this protection is not conferred upon genetic or pharmacological abolition of the catalytic activity of HDAC3. Our findings show that HDAC3 is a dichotomous transcriptional activator and repressor, with a non-canonical deacetylase-independent function that is vital for the innate immune system.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32467224,

title = {HDAC3 ensures stepwise epidermal stratification via NCoR/SMRT-reliant mechanisms independent of its histone deacetylase activity},

author = {Katherine M Szigety and Fang Liu and Chase Y Yuan and Deborah J Moran and Jeremy Horrell and Heather R Gochnauer and Ronald N Cohen and Jonathan P Katz and Klaus H Kaestner and John T Seykora and John W Tobias and Mitchell A Lazar and Mingang Xu and Sarah E Millar},

doi = {10.1101/gad.333674.119},

issn = {1549-5477},

year  = {2020},

date = {2020-07-01},

journal = {Genes Dev},

volume = {34},

number = {13-14},

pages = {973--988},

abstract = {Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. The class I HDAC, HDAC3, is of particular interest because it plays divergent roles in different tissues by partnering with tissue-specific transcription factors. We found that HDAC3 is expressed broadly in embryonic epidermis and is required for its orderly stepwise stratification. HDAC3 protein stability in vivo relies on NCoR and SMRT, which function redundantly in epidermal development. However, point mutations in the NCoR and SMRT deacetylase-activating domains, which are required for HDAC3's enzymatic function, permit normal stratification, indicating that HDAC3's roles in this context are largely independent of its histone deacetylase activity. HDAC3-bound sites are significantly enriched for predicted binding motifs for critical epidermal transcription factors including AP1, GRHL, and KLF family members. Our results suggest that among these, HDAC3 operates in conjunction with KLF4 to repress inappropriate expression of , , and  In parallel, HDAC3 suppresses expression of inflammatory cytokines through a -dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32130892,

title = {Early B Cell Factor Activity Controls Developmental and Adaptive Thermogenic Gene Programming in Adipocytes},

author = {Anthony R Angueira and Suzanne N Shapira and Jeff Ishibashi and Samay Sampat and Jaimarie Sostre-Colón and Matthew J Emmett and Paul M Titchenell and Mitchell A Lazar and Hee-Woong Lim and Patrick Seale},

doi = {10.1016/j.celrep.2020.02.023},

issn = {2211-1247},

year  = {2020},

date = {2020-03-01},

journal = {Cell Rep},

volume = {30},

number = {9},

pages = {2869--2878.e4},

abstract = {Brown adipose tissue (BAT) activity protects animals against hypothermia and represents a potential therapeutic target to combat obesity. The transcription factor early B cell factor-2 (EBF2) promotes brown adipocyte differentiation, but its roles in maintaining brown adipocyte fate and in stimulating BAT recruitment during cold exposure were unknown. We find that the deletion of Ebf2 in adipocytes of mice ablates BAT character and function, resulting in cold intolerance. Unexpectedly, prolonged exposure to cold restores the thermogenic profile and function of Ebf2 mutant BAT. Enhancer profiling and genetic assays identified EBF1 as a candidate regulator of the cold response in BAT. Adipocyte-specific deletion of both Ebf1 and Ebf2 abolishes BAT recruitment during chronic cold exposure. Mechanistically, EBF1 and EBF2 promote thermogenic gene transcription through increasing the expression and activity of ERRα and PGC1α. Together, these studies demonstrate that EBF proteins specify the developmental fate and control the adaptive cold response of brown adipocytes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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{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{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{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}

}