Nuclear Receptor Corepressors are Required for the Histone Deacetylase Activity of HDAC3 In Vivo
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ABSTRACT:
PROVIDER: PRJNA182231 | ENA |
REPOSITORIES: ENA
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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
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.
2013-01-01 | GSE42541 | GEO
Project description:We report the genomic regions enriched in Histone Deacetylase 3 (HDAC3) in mouse livers. We also report the change of HDAC3 occupancy upon DAD mutations in NCOR and SMRT. HDAC3 enriched genomic regions in WT and NS-DADm mice livers using Illumina GAIIx.
2013-01-01 | E-GEOD-42540 | biostudies-arrayexpress
Project description:We report the genomic regions enriched in Histone Deacetylase 3 (HDAC3) in mouse livers. We also report the change of HDAC3 occupancy upon DAD mutations in NCOR and SMRT.
2013-01-01 | GSE42540 | GEO
Project description:Histone deacetylase 3 (HDAC3) is unique among the HDAC superfamily of chromatin modifiers that silence transcription through enzymatic modification of histones, because interaction with nuclear receptor corepressors (NCoR1/2) is required for engagement of its catalytic activity. However, loss of HDAC3 also represses transcription. Here we report that, during lipopolysaccharide (LPS) activation of macrophages, the deacetylase activity of HDAC3 is selectively engaged at ATF3-bound enhancers that repress anti-inflammatory genes. By contrast, LPS-stimulated recruitment of HDAC3 to ATF2-bound sites without NCoR1/2 activates pro-inflammatory genes by a non-canonical mechanism whereby catalytically inactive HDAC3 stably interacts with p65. Consistent with this bimodal inflammatory modulation, deletion of HDAC3 in macrophages safeguards mice from lethal exposure to LPS, but this protection is not conferred by genetic or pharmacological abolition of HDAC3 catalytic activity. Thus, HDAC3 is a dichotomous transcriptional activator and repressor whose deacetylase-independent functions are critical in priming the innate immune system.
2020-04-30 | GSE140610 | GEO
Project description:Histone deacetylase 3 (HDAC3) is unique among the HDAC superfamily of chromatin modifiers that silence transcription through enzymatic modification of histones, because interaction with nuclear receptor corepressors (NCoR1/2) is required for engagement of its catalytic activity. However, loss of HDAC3 also represses transcription. Here we report that, during lipopolysaccharide (LPS) activation of macrophages, the deacetylase activity of HDAC3 is selectively engaged at ATF3-bound enhancers that repress anti-inflammatory genes. By contrast, LPS-stimulated recruitment of HDAC3 to ATF2-bound sites without NCoR1/2 activates pro-inflammatory genes by a non-canonical mechanism whereby catalytically inactive HDAC3 stably interacts with p65. Consistent with this bimodal inflammatory modulation, deletion of HDAC3 in macrophages safeguards mice from lethal exposure to LPS, but this protection is not conferred by genetic or pharmacological abolition of HDAC3 catalytic activity. Thus, HDAC3 is a dichotomous transcriptional activator and repressor whose deacetylase-independent functions are critical in priming the innate immune system.
2020-04-30 | GSE140581 | GEO
Project description:Histone deacetylase 3 (HDAC3) is unique among the HDAC superfamily of chromatin modifiers that silence transcription through enzymatic modification of histones, because interaction with nuclear receptor corepressors (NCoR1/2) is required for engagement of its catalytic activity. However, loss of HDAC3 also represses transcription. Here we report that, during lipopolysaccharide (LPS) activation of macrophages, the deacetylase activity of HDAC3 is selectively engaged at ATF3-bound enhancers that repress anti-inflammatory genes. By contrast, LPS-stimulated recruitment of HDAC3 to ATF2-bound sites without NCoR1/2 activates pro-inflammatory genes by a non-canonical mechanism whereby catalytically inactive HDAC3 stably interacts with p65. Consistent with this bimodal inflammatory modulation, deletion of HDAC3 in macrophages safeguards mice from lethal exposure to LPS, but this protection is not conferred by genetic or pharmacological abolition of HDAC3 catalytic activity. Thus, HDAC3 is a dichotomous transcriptional activator and repressor whose deacetylase-independent functions are critical in priming the innate immune system.
2020-04-30 | GSE140573 | GEO
Project description:Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. We find that the Class I HDAC, HDAC3, is expressed broadly in embryonic epidermis, and is required for its orderly stepwise stratification. Stability of HDAC3 protein in vivo is reliant 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 independent of its histone deacetylase activity. HDAC3 functions both in conjunction with, and independent of, KLF4 to repress premature expression of different sets of terminal differentiation genes and suppresses expression of inflammatory cytokines through a RelA-dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition. We used microarrays to determine transcriptional changes in Hdac3 deleted epidermis compared to control and Ncor1/Ncor2 deleted epidermis compared to control.
2020-08-23 | GSE137234 | GEO
Project description:Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. We find that the Class I HDAC, HDAC3, is expressed broadly in embryonic epidermis, and is required for its orderly stepwise stratification. Stability of HDAC3 protein in vivo is reliant 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 independent of its histone deacetylase activity. HDAC3 functions both in conjunction with, and independent of, KLF4 to repress premature expression of different sets of terminal differentiation genes and suppresses expression of inflammatory cytokines through a RelA-dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition.
2020-08-23 | GSE137232 | GEO
Project description:Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. We find that the Class I HDAC, HDAC3, is expressed broadly in embryonic epidermis, and is required for its orderly stepwise stratification. Stability of HDAC3 protein in vivo is reliant 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 independent of its histone deacetylase activity. HDAC3 functions both in conjunction with, and independent of, KLF4 to repress premature expression of different sets of terminal differentiation genes and suppresses expression of inflammatory cytokines through a RelA-dependent mechanism. These data identify HDAC3 as a hub coordinating multiple aspects of epidermal barrier acquisition. We used microarrays to determine transcriptional changes in Klf4 deleted epidermis compared to control.
2020-08-23 | GSE137233 | GEO