The HDAC7-TET2 epigenetic axis is essential during early B lymphocyte development
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE171855 | GEO | 2022/06/27
REPOSITORIES: GEO
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Project description:The establishment of proper epigenomic landscape is essential during B lymphocyte development in order to acquire a correct B cell identity at each cellular differentiation stage. We previously identified HDAC7 as a critical regulator of early B cell development. Its absence indeed led to the aberrant activation of inappropriate lineage genes, a reduction of proliferation and an increase in cell apoptosis. More recently, we have demonstrated that HDAC7 loss in infant pro-B-ALL associates with poor prognosis. Here we shed light into the HDAC7-mediated molecular mechanisms during early B cell development. HDAC7 deficiency drives not only the expression of inappropriate lineage genes, but also global chromatin de-condensation and deregulation of epigenetic regulators of DNA methylation and potential damaging elements. Specifically, HDAC7 absence induces the expression of TET2, which promotes DNA 5-hydroxymethylation and aberrant gene activation. HDAC7 deficiency also results in the uncontrolled expression of microRNAs and non-coding elements such as LINE-1 transposable elements. These findings are relevant for the mechanistic explanation of why HDAC7 is affected in multiple B-related hematological malignancies. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for histone modifications H3K27ac and H3K27me3 in murine pro-B lymphocytes.
2022-06-27 | GSE204673 | GEO
Project description:The establishment of proper epigenomic landscape is essential during B lymphocyte development in order to acquire a correct B cell identity at each cellular differentiation stage. We previously identified HDAC7 as a critical regulator of early B cell development. Its absence indeed led to the aberrant activation of inappropriate lineage genes, a reduction of proliferation and an increase in cell apoptosis. More recently, we have demonstrated that HDAC7 loss in infant pro-B-ALL associates with poor prognosis. Here we shed light into the HDAC7-mediated molecular mechanisms during early B cell development. HDAC7 deficiency drives not only the expression of inappropriate lineage genes, but also global chromatin de-condensation and deregulation of epigenetic regulators of DNA methylation and potential damaging elements. Specifically, HDAC7 absence induces the expression of TET2, which promotes DNA 5-hydroxymethylation and aberrant gene activation. HDAC7 deficiency also results in the uncontrolled expression of microRNAs and non-coding elements such as LINE-1 transposable elements. These findings are relevant for the mechanistic explanation of why HDAC7 is affected in multiple B-related hematological malignancies. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed in murine pro-B and pre-B lymphocytes.
2022-06-27 | GSE204672 | GEO
Project description:B lymphocyte development is a complex process tightly controlled at the transcriptional level by the action of networks of transcription factors. The repression of genes from alternative lineages is necessary to ensure the acquisition of the correct B cell identity. However, the mechanisms of transcriptional repression during B cell generation are largely unknown. Here, using a conditional knockout mouse model, we show that the histone deacetylase HDAC7 is essential for B cell development. Early deletion of HDAC7 dramatically blocked B cell development at the pro-B cell stage and gave rise to a severe lymphopenia in peripheral organs. HDAC7-deficient pro-B cells exhibit cell lineage promiscuity, expressing myeloid and T lymphocyte genes. In wild-type B cells HDAC7 is recruited to myocyte enhancer factor 2C (MEFC2) binding sites located at the promoters of macrophage and T lymphocyte genes. Our results demonstrate that HDAC7 is a bona fide transcriptional repressor essential for B cell development.
2016-09-26 | GSE66163 | GEO
Project description:B lymphopoiesis is the result of several cell lineage choices and differentiation steps whose perturbation leads to B cell malignancies. Cellular transitions for B cell generation have been associated with gene activation and silencing by networks of B cell specific transcription factors (TFs) and dynamic changes in DNA methylation. How gene repression is established and which lineage-specific transcriptional repressors are involved during B cell lymphopoiesis are still not totally understood. Here, by using our in vivo experimental approach, we have found that HDAC7 represses Tet2 enzyme in pro-B cells. In fact, HDAC7 deficient pro-B cells show a significant increase in the percentage of global 5-hydroxymethylation. To prove the role of HDAC7 in 5-hydroxymethylation, we have performed a genome-wide experimental approach. hMeDIP-sequencing experiments reveal an increase in the enrichment of this epigenetic modification at many loci related to lineage inappropriate genes. Our results corroborate that HDAC7 is an essential transcriptional regulator during early B cell development that silences lineage or functionally inappropriate genes and unveil an unexpected role of a class IIa HDAC in controlling DNA methylation
2022-06-28 | GSE135263 | GEO
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
Project description:Histone deacetylase 7 (HDAC7) is highly expressed in CD4+/CD8+ thymocytes and functions as a signal-dependent repressor of gene transcription during T cell development. In this study, we express HDAC7 mutant proteins in a T cell line and use DNA microarrays to identify transcriptional targets of HDAC7 in T cells. Gene expression changes are compared to differential gene expression profiles associated with positive and negative thymic selection. This analysis reveals that HDAC7 regulates an extensive set of genes that are differentially expressed during both positive and negative thymic selection. Many of these genes play important functional roles in positive and negative selection, primarily via coupling between antigen receptor and downstream signaling events. Keywords: microarray gene expression profiling, comparison of perturbation of HDAC7 gene function with differential expression during thymic selection
2007-11-04 | GSE7468 | GEO
Project description:Overexpression HDAC7 can enhance iPS efficiency in SKO by supressing MEF2 factors We used microarrays to identify changes induced by overexpression of HDAC7 or MEF2C. MEFs were transduced with SKO plus HDAC7 or MEF2C compared to SKO plus empty vector(Flag), GFP as controls. TRIZOL cell lysates were prepared from D6 and D10.
2011-08-17 | E-GEOD-23692 | biostudies-arrayexpress
Project description: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 Jalpha 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. Title of manuscript: Nuclear Export of Histone Deacetylase 7 During Thymic Selection Mediates Immune Self-tolerance. abstract of manuscript: Histone Deacetylase 7 (HDAC7) is a TCR signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-?P) in thymocytes. We find that HDAC7-?P Transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression program in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance. 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.
2011-04-06 | GSE26488 | GEO
Project description:In the immune system HDAC7 is expressed in T cells where it regulates the expression of key genes for T cell development and function. Here we report that HDAC7 is also highly expressed in B cell precursors, where it is recruited by MEF2C to repress the activity of key genes for myeloid cell function. While HDAC7 is down-regulated during the conversion of pre-B cells into macrophages, re-expression of HDAC7 interferes with both the acquisition of the myeloid gene transcriptional program and macrophage specific cell functions. Thus, HDAC7 is a novel transcriptional repressor of lineage inappropriate genes in B cells.
2014-03-25 | GSE36827 | GEO
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