Dichotomous Engagement of HDAC3 Activity Governs Inflammatory Responses
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ABSTRACT:
PROVIDER: PRJNA590241 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Dichotomous Engagement of HDAC3 Activity Governs Inflammatory Responses [ChIP-Seq]
| PRJNA590208 | ENA
Project description:Dichotomous Engagement of HDAC3 Activity Governs Inflammatory Responses [RNA-Seq]
| PRJNA590243 | ENA
Project description:Dichotomous Engagement of HDAC3 Activity Governs Inflammatory Responses [GRO-Seq]
| PRJNA590194 | ENA
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: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 activity1-3. However, global loss of HDAC3 also results in the repression of transcription, the mechanism of which is currently unclear4-8. 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.
| S-EPMC7725280 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-04-30 | GSE140611 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE33162: HDAC3 requirement for the inflammatory gene expression program in macrophages [gene expression] GSE33163: HDAC3 requirement for the inflammatory gene expression program in macrophages [ChIP_Seq] Refer to individual Series
2012-07-08 | E-GEOD-33164 | biostudies-arrayexpress
Project description:Pan-Hdac inhibitors (HDACi) are endowed with a potent anti-inflammatory activity, but the relative role of each of the eleven Hdac proteins sensitive to HDACi to the inflammatory gene expression program is unknown. Using an integrated genomic approach we found that Hdac3-deficient macrophages are unable to activate almost half of the inflammatory gene expression program when stimulated with lipopolysaccharide (LPS). A large part of the activation defect is due to loss of basal and LPS-inducible expression of IFNb, which in basal cells maintains Stat1 protein levels, and after stimulation acts in an autocrine/paracrine manner to promote a secondary wave of Stat1-dependent gene expression. We show that loss of Hdac3-mediated repression of nuclear receptors leads to hyperacetylation of thousands of genomic sites and associated gene derepression. The upregulation of the constitutively expressed prostaglandin endoperoxide synthase, Ptgs1 (Cox-1), has a causative role in the phenotype, since its chemical inhibition reverts the Ifnb activation defect. These data may have relevance for the use of selective Hdac inhibitors as anti-inflammatory agents. Chromatin immuno-precipitations of H4 histone pan-acetylation followed by multiparallel sequencing performed in murine bone marrow-derive macrophages. Experiments carried out in untreated cells as well as in cells treated for 4hrs with lipopolysaccharide (LPS), for both HDAC3 +/- (wt) and HDAC3 -/- (KO) mice.
2012-07-08 | E-GEOD-33163 | biostudies-arrayexpress