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Nuclear Receptor Corepressors Non-Canonically Drive Glucocorticoid Receptor-Dependent Activation of Hepatic Gluconeogenesis [ATAC-Seq]

ABSTRACT: Nuclear receptor corepressors (NCORs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3). In the liver, loss of HDAC3 causes a marked hepatosteatosis largely due to derepression of genes involved in lipid metabolism. Here we show that adult loss of both NCOR1 and 2 (dKO) in hepatocytes phenocopies the hepatomegalic fatty liver phenotype. In addition, dKO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCORs nor HDAC3, resulting in profound fasting hypoglycemia. This surprising HDAC3-independent activation function of NCOR1/2 was due to an unexpected loss of chromatin accessibility upon 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE234233 | GEO | 2024/02/22

REPOSITORIES: GEO

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Nuclear Receptor Corepressors Non-Canonically Drive Glucocorticoid Receptor-Dependent Activation of Hepatic Gluconeogenesis [ChIP-Seq]

Project description:Nuclear receptor corepressors (NCORs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3). In the liver, loss of HDAC3 causes a marked hepatosteatosis largely due to derepression of genes involved in lipid metabolism. Here we show that adult loss of both NCOR1 and 2 (dKO) in hepatocytes phenocopies the hepatomegalic fatty liver phenotype. In addition, dKO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCORs nor HDAC3, resulting in profound fasting hypoglycemia. This surprising HDAC3-independent activation function of NCOR1/2 was due to an unexpected loss of chromatin accessibility upon 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.

2024-02-22 | GSE252681 | GEO

Nuclear Receptor Corepressors Non-Canonically Drive Glucocorticoid Receptor-Dependent Activation of Hepatic Gluconeogenesis [RNA-Seq]

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Balanced Control of Thermogenesis by Nuclear Receptor Corepressors in Brown Adipose Tissue

Project description: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 requires histone deacetylase 3 (HDAC3). HDAC3 exists in tight association with nuclear receptor corepressors NCoR1 and NCoR2(also known as Silencing Mediator of Retinoid and Thyroid Receptors, or SMRT), butthe 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 the NCoR1/2 BAT-dKO and HDAC3 BAT KO mice. Despite these commonalities, however, loss of NCoR1/2 in BAT does not phenocopy the cold sensitivity observed in the HDAC3 BAT-KO, nor does loss of either corepressor alone. Instead, BAT lacking NCoR1/2 is inflamed, particularly with respect to the IL-17 axis that increases thermogenic capacity by enhancing innervation. Integration of BAT RNA-seq and ChIP-seq data revealed that NCoR1/2 directly regulate Mmp9, 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 their stimulation of HDAC3 activity in the control of thermogenesis.

2022-07-27 | GSE199808 | GEO

Nuclear Receptor Corepressors are Required for the Histone Deacetylase Activity of HDAC3 In Vivo

Project description:Histone deacetylase 3 (HDAC3) is an epigenome-modifying enzyme that is required for normal mouse development and tissue-specific functions. In vitro, HDAC3 protein itself has minimal enzyme activity, but gains its histone deacetylation function from stable association with the conserved deacetylase activation domain (DAD) contained in nuclear receptor corepressors NCOR1 and SMRT. Here we show that HDAC3 enzyme activity is undetectable in mice bearing point mutations in the DAD of both NCOR1 and SMRT (NS-DADm), despite normal levels of HDAC3 protein. Local histone acetylation is increased, and genomic HDAC3 recruitment is reduced though not abrogated. Remarkably, the NS-DADm mice are born and live to adulthood, whereas genetic deletion of HDAC3 is embryonic lethal. These findings demonstrate that nuclear receptor corepressors are required for HDAC3 enzyme activity in vivo, and suggest that a deacetylase-independent function of HDAC3 may be required for life. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series.

2013-01-01 | E-GEOD-42541 | biostudies-arrayexpress

Nuclear Receptor Corepressors are Required for the Histone Deacetylase Activity of HDAC3 In Vivo

2013-01-01 | GSE42541 | GEO

Nuclear receptor corepressor (NCOR) and HDAC3 in hypothalamus [ChIP-Seq]

Project description:We determined genomic binding of HDAC3 in mouse hypothalamus by ChIP-seq, and identified target genes of the NCOR/HDAC3 complex in hypothalamus of NS-DADm (mutated deacetylase activation domain in NCORs) mice by RNA-seq.

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Nuclear receptor corepressor (NCOR) and HDAC3 in hypothalamus [RNA-Seq]

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Project description:The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein we demonstrate that NCOR1/2 deletion limits B cell differentiation via impaired recombination, attenuates pre-BCR-signaling, and enhances STAT5-dependent transcription. Furthermore, NCOR1/2-deficient B cells exhibited derepression of EZH2-repressed gene modules, including the p53 pathway. These alterations resulted in aberrant Rag1 and Rag2 expression and accessibility in proliferating cells. Whole-genome sequencing of Ncor1/2 DKO B cells identified increased number of structural variants compared to wildtype B cells with cryptic recombination signal sequences. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, while human leukemias with less NCOR1 correlated with worse survival. NCOR1 mutations in human leukemia correlated with increased RAG expression and increased number of structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations may promote B cell transformation.

2022-08-30 | GSE208656 | GEO

Corepressors NCOR1 and SMRT regulate metabolism via intestinal regulation of carbohydrate transport

Project description:Objective: Nuclear receptor action is mediated in part by the nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT; also known as NCOR2). NCOR1 and SMRT regulate metabolic pathways that govern body mass, insulin sensitivity and energy expenditure and represent an understudied area in the realm of metabolic health and disease. Previously, we found that NCOR1 and SMRT are essential for maintaining metabolic homeostasis and their knockout (KO) leads to rapid weight loss and hypoglycemia, which is not survivable. Because of a potential defect in glucose absorption, we sought to determine the role of NCOR1 and SMRT specifically in intestinal epithelial cells (IECs). Methods: We used a post-natal strategy to disrupt NCOR1 and SMRT throughout IECs in adult mice. These mice were characterized metabolically by assessing body weight, glucose levels and subjecting the mice to metabolic phenotyping, body composition analysis and glucose tolerance testing. IECs were isolated from the jejunum of the small intestine and profiled by bulk RNA sequencing. Results: We found that the post-natal KO of NCOR1 and SMRT from IECs leads to rapid weight loss and hypoglycemia with a significant reduction in survival. This was accompanied by alterations in glucose metabolism and activation of fatty acid oxidation in IECs. Metabolic phenotyping confirmed a reduction in body mass driven by a loss of body fat without any difference in food intake. This appeared to be driven by a reduction of key intestinal carbohydrate transporters, including SGLT1, GLUT2 and GLUT5. Conclusions: Intestinal NCOR1 and SMRT act in tandem to regulate glucose levels and body weight. This in part may be mediated by regulation of intestinal carbohydrate transporters.

2024-08-12 | GSE268594 | GEO

Nuclear Receptor Corepressors are Required for the Histone Deacetylase Activity of HDAC3 In Vivo (ChIP-Seq)

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2013-01-01 | E-GEOD-42540 | biostudies-arrayexpress

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