Control of Th17 cell development by Class IIa HDAC4 and HDAC7 through transcriptional repression of negative regulators
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE92531 | GEO | 2018/12/16
REPOSITORIES: GEO
Similar Datasets
Project description:Histone deacetylases (HDACs) are long recognized for important functions in regulating gene transcription in biology and diseases. However, unlike for ubiquitously expressed class I HDACs, we have little mechanistic understanding of class II HDACs that have postulated tissue specific functions. Here we report that class IIa Hdac4 and Hdac7 are up-regulated in transcription through IL-6-Stat3 signaling selectively in mouse T-helper 17 (Th17) cells during lineage-specific differentiation, but not in Th1, Th2, and Treg subtypes. Genetic knockout of Hdac4 or Hdac7 established their importance for Th17 differentiation with different functional mechanisms. Hdac4 works with Th17 transcription factors JunB-Irf4-Batf for transcriptional activation of Th17 signature genes Il17a/f, whereas Hdac7 acts distinctively in concert with Aiolos/Ncor1/Hdac3 co-repressor complex for transcriptional repression of Th17 negative regulators including Il2. Pharmacological inhibition or gene knockout of Hdac4 and Hdac7 ameliorates development of T-cell transfer induced colitis and experimental autoimmune encephalomyelitis (EAE) in mice through blockage of Th17 cell development in colon and central nervous system that recapitulate inflammatory bowel diseases and multiple sclerosis in humans, respectively. Our study highlights a previously unknown distinct mechanisms of Hdac4 and Hdac7 in transcriptional control of Th17 cell development, and rationalizes a new therapeutic strategy of targeting class IIa HDAC4/7 for the treatment of Th17-related inflammatory and autoimmune diseases.
2023-02-03 | GSE144830 | GEO
Project description:Our class IIa HDAC inhibitor, NVS-HD1, inhibited HDAC4 with less than 1 nM potency while exhibiting >200 fold selectivity on class IIa HDACs compared to class I (HDAC1, 3, 8) and class IIb (HDAC6) HDACs, making it the most potent and selective class IIa HDAC inhibitor reported so far. We tested the efficacy of NVS-HD1 in the mouse denervation model, either alone or on the genetic background of HDAC4 whole-body inducible knockout (HDAC4 iRKO). Global gene expression changes in gastrocnemius muscles were profiled by RNAseq. In the innervated control legs, HDAC4 knockout or NVS-HD1 caused little changes in gene expression compared to WT mice. HDAC4 knockout or NVS-HD1 mainly reversed denervation induced changes and the genes regulated by them largely overlap, suggesting that NVS-HD1 is quite specific against class IIa HDACs.
2019-11-27 | GSE136627 | GEO
Project description:Access to DNA is the first level of control in regulating gene transcription, a control that is also critical for maintaining DNA integrity. Cellular senescence is characterized by profound transcriptional rearrangements and accumulation of DNA lesions. Here, we discovered an epigenetic complex between HDAC4 and HDAC1/HDAC2 that is involved in the erase of H2BK120 acetylation. The HDAC4/HDAC1/HDAC2 complex modulates the efficiency of DNA repair by homologous recombination, through dynamic deacetylation of H2BK120. Deficiency of HDAC4 leads to accumulation of H2BK120ac, impaired recruitment of BRCA1 and CtIP to the site of lesions, accumulation of damaged DNA and senescence. In senescent cells this complex is disassembled because of increased proteasomal degradation of HDAC4. Forced expression of HDAC4 during RAS-induced senescence reduces the genomic spread of γH2AX and affects H2BK120ac levels, which are increased in DNA-damaged regions accumulated during RAS-induced senescence. In summary, degradation of HDAC4 during senescence causes the accumulation of damaged DNA and contributes to the activation of the transcriptional program controlled by super-enhancers that maintains senescence.
2024-10-17 | PXD051316 | Pride
Project description:HDACs play crucial role in epigenetic modulation through deacetylation of histone and non-histone substrates in critical process of normal development and cancer. Moreover, HDAC inhibitors have been considered as new agent by effects such as cell cycle arrest, apoptosis, anti-angiogenic effects and autophagy and utilized in clinical applications for chemotherapy. we previously reported that HDAC 1, 4, 6 and 8 were higly expressed in MDA-MB-231 than MCF-7 cells and HDAC1, 6 and 8 excepting HDAC4 were associated with invasion that is very important factor in cancer progression. However, HDAC4 did not affect in invasion. To investigate interaction between chemoresistance and HDAC4 expression, we establish stable cells overexpressing HDAC4 in MCF-7 cells. Cells overexpressed HDAC4 were increased cytotoxicity about 5-FU and identified 356 differentially expressed genes using Ilumina array. Based on array result, we selected SMAD4 as a candidate gene related with chemoresistance because SMAD4 was previously reported evaluation of chemoresistance to 5-FU. We purpose that HDAC4 regulated with SMAD4 expression through acetylation in SMAD4 promoter region. HDAC4 directly bound a part of SMAD4 promoter. Total RNA obtained from cells overexpressed HDAC4 cDNA in MCF-7 compared to control cells.
2013-11-01 | E-GEOD-42242 | biostudies-arrayexpress
Project description:Purpose: We performed RNA-seq differential expression analysis after 72h HDAC1 and HDAC7 knockdown in order to evaluate the transcriptional regulation exerted by HDAC1 and HDAC7 in a stem-like (BPLER) vs. non-stem (HMLER) breast cancer (BrCa) cell model (please search for keywords "BPLER" or "HMLER" in GEO to access over 240 associated data sets). Results: HDAC7 knockdown by a pool of siRNAs resulted in altered expression of nearly three times the genes in BPLER vs. HMLER cells (2545 vs. 763), with the two cell types sharing altered expression of 328 genes. In stem-like BPLER cells, HDAC7 knockdown caused significant alterations in gene expression (1068 down and 1477 up). Fewer genes, less than half of BPLER, were altered in non-stem HMLER cells (448 down and 315 up), with 199 repressed and 129 activated genes shared between the two cell types. In contrast, 72h HDAC1 knockdown resulted in nearly equal numbers of altered genes in BPLER vs. HMLER cells (3187 vs. 2627), with the two cell types sharing altered expression of 637 genes. Moreover, the number of repressed (1570 vs. 1307) and activated (1617 vs. 1320) gene transcripts was similar in the two cell types In HMLER cells, HDAC7 knockdown resulted in alterations of significantly fewer gene transcripts compared to HDAC1 knockdown (508 vs. 2681), in both repressed (305 vs. 1362) and activated (203 vs. 1319) transcripts. Conclusions: Cumulatively, these results highlight that HDAC7 regulates nearly three times as many genes in stem-like compared to non-stem BrCa cells. In contrast, HDAC1 regulates equal number of genes in the same cell context, suggesting a predominant association of HDAC7 with the cancer stem cell phenotype.
2020-02-24 | GSE131631 | GEO
Project description:HDACs play crucial role in epigenetic modulation through deacetylation of histone and non-histone substrates in critical process of normal development and cancer. Moreover, HDAC inhibitors have been considered as new agent by effects such as cell cycle arrest, apoptosis, anti-angiogenic effects and autophagy and utilized in clinical applications for chemotherapy. we previously reported that HDAC 1, 4, 6 and 8 were higly expressed in MDA-MB-231 than MCF-7 cells and HDAC1, 6 and 8 excepting HDAC4 were associated with invasion that is very important factor in cancer progression. However, HDAC4 did not affect in invasion. To investigate interaction between chemoresistance and HDAC4 expression, we establish stable cells overexpressing HDAC4 in MCF-7 cells. Cells overexpressed HDAC4 were increased cytotoxicity about 5-FU and identified 356 differentially expressed genes using Ilumina array. Based on array result, we selected SMAD4 as a candidate gene related with chemoresistance because SMAD4 was previously reported evaluation of chemoresistance to 5-FU. We purpose that HDAC4 regulated with SMAD4 expression through acetylation in SMAD4 promoter region. HDAC4 directly bound a part of SMAD4 promoter.
2013-11-01 | GSE42242 | GEO
Project description:Purpose: Define the transcriptional networks supervising class IIa HDAC expression. Outcome: We demonstrate that MEF2D is the key factor controlling HDAC9 transcription. Comprehensive genome-wide studies demonstrate that HDAC4 and HDAC9 supervise different genetic programs and show both specific and common genomic bindings. Although the number of MEF2-target genes commonly regulated is similar, only HDAC4 represses many additional genes that are not MEF2D targets. HDAC4-/- and HDAC9-/- cells increase H3K27ac levels around the TSS of the respective repressed genes. However, these genes rarely show bindings of the HDACs at their promoters. Frequently HDAC4 and HDAC9 bind intergenic regions. We demonstrate that these regions, recognized by MEF2D/HDAC4/HDAC9 repressive complexes, show the features of active enhancers.
2019-11-13 | GSE132569 | GEO
Project description:Purpose: Define the transcriptional networks supervising class IIa HDAC expression. Outcome: We demonstrate that MEF2D is the key factor controlling HDAC9 transcription. Comprehensive genome-wide studies demonstrate that HDAC4 and HDAC9 supervise different genetic programs and show both specific and common genomic bindings. Although the number of MEF2-target genes commonly regulated is similar, only HDAC4 represses many additional genes that are not MEF2D targets. HDAC4-/- and HDAC9-/- cells increase H3K27ac levels around the TSS of the respective repressed genes. However, these genes rarely show bindings of the HDACs at their promoters. Frequently HDAC4 and HDAC9 bind intergenic regions. We demonstrate that these regions, recognized by MEF2D/HDAC4/HDAC9 repressive complexes, show the features of active enhancers.
2019-11-12 | GSE132622 | GEO
Project description:Analysis of Class II Histone Deacetylase (HDAC) regulation of hepatic gluconeogenesis at the gene expression level. We show that in liver, Class IIa HDACs (HDAC4, 5, and 7) are all phosphorylated and excluded from the nucleus by AMPK family kinases. In response to the fasting hormone glucagon, Class IIa HDACs rapidly translocate to the nucleus where they directly bind to the promoters of gluconeogenic enzymes such as G6Pase. In turn, HDAC4/5 mediate the acute transcriptional induction of these genes via deacetylation and activation of Foxo family transcription factors. Loss of Class IIa HDACs in the murine liver results in inhibition of FOXO target genes and lowers blood glucose, resulting in increased glycogen storage. Total RNA obtained from primary hepatocytes infected with shGFP or shHDAC4 & 5 subjected to 2 or 4 hours treatment with DMSO or forskolin.
2011-09-08 | E-GEOD-20979 | biostudies-arrayexpress
Project description:Title of Publication: Histone Deacetylase 7 Regulates Cell Survival and TCR Signaling in CD4/CD8 Double-Positive Thymocytes Abstract of publicaton: CD4/CD8 double-positive (DP) thymocytes express the transcriptional repressor Histone Deacetylase 7 (HDAC7), a class IIa HDAC that is exported from the cell nucleus after T cell receptor (TCR) engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in thymocytes, and regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR J segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAP kinase activity that contributes to the observed loss of viability. Remarkably, the activity of Protein Kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining auto-excitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions. Goal of Microarray experiment: We did these experiments to determine how alteration of the function of HDAC7, a site-specific and signal-dependent repressor of transcription, changes gene expression in CD4/CD8 DP thymocytes. Three biological replicate samples were prepared for each non-wild type mouse strain (Samples 7-18). Six biological replicates were prepared for the wild type strain (Samples 1-6). Total RNA was prepared from isolated CD4/CD8 Double-positive thymocytes and labeled with the Affymetrix Whole-Transcript labeling protocol. Labeled probes were hybridized to one Affymetrix Mouse Gene 1.0ST array each. Data from .cel files were normalized using RMA, in normalization groups representing each of the binary comparisons made. These binary comparisons between sample groups represent gene expression changes due to loss of HDAC7 (samples 1-3 vs. 7-9), transgenic expression of an HDAC7-VP16 fusion protein (samples 4-6 vs. 10-12), positive thymic selection (samples 1-6 vs. samples 11-15), and negative thymic selection (Samples 11-15 vs. samples 16-18).
2011-04-06 | E-GEOD-26488 | biostudies-arrayexpress