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.
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.
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.
Project description:We profiled gene expression in livers depleted of NCOR (nuclear receptor corepressor) along with wild-type livers as control. NCOR floxed mice were intravenously injected with adeno-associated virus (AAV) expressing Cre or GFP. Livers were harvested at 2-weeks post-injection at 5pm (ZT10). Total RNA was extracted and hybridized to Affymetrx Mouse Gene 2.0 array.
Project description:We reported a diurnal changes in the recruitment of HDAC3, Rev-erbα, NCoR and Pol II to the mouse liver genome as well as H3K9 acetylation in vivo at ZT10 and ZT22. ChIP-Seq profiling of HDAC3, Rev-erbα, NCoR and Pol II binding and H3K9Ac in mouse liver harvested at 2 different times (ZT10 and ZT22) of the day
Project description:Obesity-associated lipid overload triggers non-alcoholic fatty liver diseases (NAFLD), which in part may be driven by alterations of regulatory transcription networks and hepatocyte-selective epigenomes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR)/ histone deacetylase 3 (HDAC3) complex, is a central component of such networks and accelerates the progression of non-alcoholic steatohepatitis (NASH). In hepatocyte-specific Gps2 knockout mice, loss of GPS2 alleviated the development of diet-induced steatosis and fibrosis and caused activation of lipid catabolic genes. By determining differential cistromes, epigenomes and transcriptomes in wild-type, single and double knockout mice, we identified the lipid-sensing nuclear receptor PPARa as a direct target of GPS2. We also provide evidence that in hepatocytes, unlike in macrophages, GPS2 acts in concert with the NCOR subunit of the corepressor complex. By analyzing the liver transcriptomes of human patients, we found that GPS2 expression positively correlated with the expression of NASH/fibrosis signature genes. Collectively, our data suggest that the GPS2-PPARa partnership in hepatocytes may influence the development of NASH/fibrosis in mice and in humans.
Project description:To investigate the genomic localization of NCoR/HDAC3/PGC1β complex and the enhancer/promoter activity in inflammatory genes, we used NCoR KO or PGC1β KO bone marrow-derived macrophages and Traf6 siRNA knockdown bone marrow-derived macrophages. We then performed chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for H3K27ac, NCoR, HDAC3, PGC1β, ERK1, p65, Fosl2, PU.1 and p300.
