HDAC6 deacetylates IDH1 to regulate the homeostasis of hematopoietic stem/progenitor cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA839243 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24062652_1.fastq.gz | Fastqsanger.gz | |||
| SRR24062652_2.fastq.gz | Fastqsanger.gz | |||
| SRR24062653_1.fastq.gz | Fastqsanger.gz | |||
| SRR24062653_2.fastq.gz | Fastqsanger.gz | |||
| SRR24062654_1.fastq.gz | Fastqsanger.gz |
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Project description:HDAC6 deacetylates IDH1 to regulate the homeostasis of hematopoietic stem/progenitor cells [WGBS-seq]
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Project description:In order to further explore the mechanism by which increased 5hmC inhibits expansion of LSK cells from Hdac6-/- murine primary BM cells, we performed RNA sequencing (RNA-seq) analysis using LSK cells isolated from Hdac6-/- and WT mice.
2022-05-21 | GSE203239 | GEO
Project description:In order to further explore the mechanism by which increased 5hmC inhibits expansion of LSK cells from Hdac6-/- murine primary BM cells, we performed WGBS-seq and oxWGBS-seq analysis using LSK cells isolated from Hdac6-/- and WT mice.
2023-06-06 | GSE234147 | GEO
Project description:Hematopoietic stem and progenitor cells (HSPCs) are cells mainly present in the bone marrow and capable of forming mature blood cells. However, the epigenetic mechanisms governing the homeostasis of HSPCs remain elusive. Here we demonstrate an important role for histone deacetylase 6 (HDAC6) in regulating this process. Our data show that the percentage of HSPCs in Hdac6 knockout mice is lower than in wild-type mice, due to decreased HSPC proliferation. HDAC6 interacts with isocitrate dehydrogenase 1 (IDH1) and deacetylates IDH1 at lysine 233. The deacetylation of IDH1 inhibits its catalytic activity and thereby decreases the 5-hydroxymethylcytosine level of ten-eleven translocation 2 (TET2) target genes, changing gene expression patterns to promote the proliferation of HSPCs. These findings uncover a role for HDAC6 and IDH1 in regulating the homeostasis of HSPCs and may have implications for the treatment of hematological diseases.
| S-SCDT-10_15252-EMBR_202256009 | biostudies-other
Project description:Foxp3+ T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3+ Tregs express histone/protein deacetylases (HDACs) that regulate chromatin remodeling, gene expression and protein function. Pan-HDAC inhibitors developed for oncology enhance Treg production and suppression but have limited non-oncologic applications given their broad effects. We show, using HDAC6-deficient mice and WT mice treated with HDAC6-specific inhibitors, that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, including multiple forms of experimental colitis and fully MHC-incompatible cardiac allograft rejection. Many of the beneficial effects of HDAC6 targeting are also achieved by inhibition of the HDAC6-regulated protein, HSP90. Hence, selective targeting of a single HDAC isoform, HDAC6, or its downstream target, HSP90, can promote Treg-dependent suppression of autoimmunity and transplant rejection. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of HDAC6 knock out, compared to wild type (C57BL6) control
2011-05-01 | E-GEOD-27896 | biostudies-arrayexpress
Project description:Foxp3+ T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3+ Tregs express histone/protein deacetylases (HDACs) that regulate chromatin remodeling, gene expression and protein function. Pan-HDAC inhibitors developed for oncology enhance Treg production and suppression but have limited non-oncologic applications given their broad effects. We show, using HDAC6-deficient mice and WT mice treated with HDAC6-specific inhibitors, that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, including multiple forms of experimental colitis and fully MHC-incompatible cardiac allograft rejection. Many of the beneficial effects of HDAC6 targeting are also achieved by inhibition of the HDAC6-regulated protein, HSP90. Hence, selective targeting of a single HDAC isoform, HDAC6, or its downstream target, HSP90, can promote Treg-dependent suppression of autoimmunity and transplant rejection.
2011-05-01 | GSE27896 | GEO
Project description:Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequent in human glioblastomas1 and cytogenetically normal acute myeloid leukemias (AML)2. These alterations are gain-of-function mutations in that they drive the synthesis of the M-bM-^@M-^\oncometaboliteM-bM-^@M-^] R-2-hydroxyglutarate (2HG)3. It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukemogenesis. Here we report the characterization of conditional knock-in mice in which the most common IDH1 mutation, Idh1-R132H, is inserted into the endogenous murine Idh1 locus and is expressed in cells of the hematopoietic (Vav-KI) or more specifically in cells of the myeloid (LysM-KI) lineage. These mutants show increased numbers of early hematopoietic progenitors and develop splenomegaly and anemia with extramedullary hematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells exhibit both hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1/2-mutant AML. Thus, our study is the first to describe the generation of conditional Idh1-R132H-KI mice. Furthermore, our study is also the first report showing the induction of a leukemic DNA methylation signature in a modeled system and sheds light on the mechanistic links between IDH1 mutation and human AML. DNA methylation profiling in LSK cells from IDH1-R132H knock-in mice vs. control mice
2012-07-22 | E-GEOD-38687 | biostudies-arrayexpress
Project description:The Tip60 (also known as Kat5) lysine acetyltransferase functions broadly as a transcriptional co-activator that acetylates histones. In contrast, Tip60 functions in embryonic stem cells (ESCs) both to silence genes that promote differentiation and to activate genes required for proliferation. The mechanism by which Tip60 functions as a repressor is unknown. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs and is necessary for complete silencing of most differentiation genes targeted by Tip60. In contrast to differentiated cells, where Hdac6 is mainly cytoplasmic and does not interact with Tip60, Hdac6 is largely nuclear in ESCs and neural stem cells (NSCs) and interacts with Tip60-p400 in both cell types. Hdac6 is enriched at promoters bound by Tip60-p400 in ESCs, but while Tip60 binds on both sides of transcription start sites (TSSs), Hdac6 binding overlaps with only the downstream Tip60 peak. Surprisingly, Hdac6 does not deacetylate histones at these sites, but rather is required for Tip60 binding. These data suggest that nuclear exclusion of Hdac6 during differentiation plays a major role in modulation of Tip60-p400 function. We determined the genome-wide localization of Tip60 and Hdac6 in mouse ES cells, and examined genomic binding profiles of Tip60 and Hdac6 upon indicated knockdown by ChIP-seq. We examined genomic binding profiles of p400 upon indicated knockdown by ChIP-seq.
2013-11-20 | E-GEOD-42209 | biostudies-arrayexpress
Project description:Histone deacetylases (HDACs) are crucial regulators of gene expression, DNA synthesis, and cellular processes, making them essential targets in cancer research. HDAC6, specifically, influences protein stability and chromatin dynamics. Despite HDAC6's potential therapeutic value, its exact role in gene regulation and chromatin remodeling needs further clarification. This study examines how HDAC6 inactivation influences lysine acetyltransferase P300 stabilization and subsequent effects on chromatin structure and function in cancer cells. We employed the HDAC6 inhibitor ITF3756, siRNA, or CRISPR/Cas9 gene editing to inactivate HDAC6 in different epigenomic backgrounds. Constantly, this inactivation led to significant changes in chromatin accessibility, particularly increased acetylation of histone H3 lysines 9, 14, and 27 (ATAC-seq and H3K27Ac ChIP-seq analysis). Transcriptomics, proteomics, and gene ontology analysis revealed gene changes in cell proliferation, adhesion, migration, and apoptosis. Significantly, HDAC6 inactivation altered P300 ubiquitination, stabilizing P300 and leading to downregulating genes critical for cancer cell survival. Our study highlights the substantial impact of HDAC6 inactivation on the chromatin landscape of cancer cells and suggests a role for P300 in contributing to the anticancer effects. The stabilization of P300 with HDAC6 inhibition proposes a potential shift in therapeutic focus from HDAC6 itself to its interaction with P300. This finding opens new avenues for developing targeted cancer therapies, improving our understanding of epigenetic mechanisms in cancer cells.
2024-08-19 | GSE273645 | GEO
Project description:Histone deacetylases (HDACs) are crucial regulators of gene expression, DNA synthesis, and cellular processes, making them essential targets in cancer research. HDAC6, specifically, influences protein stability and chromatin dynamics. Despite HDAC6's potential therapeutic value, its exact role in gene regulation and chromatin remodeling needs further clarification. This study examines how HDAC6 inactivation influences lysine acetyltransferase P300 stabilization and subsequent effects on chromatin structure and function in cancer cells. We employed the HDAC6 inhibitor ITF3756, siRNA, or CRISPR/Cas9 gene editing to inactivate HDAC6 in different epigenomic backgrounds. Constantly, this inactivation led to significant changes in chromatin accessibility, particularly increased acetylation of histone H3 lysines 9, 14, and 27 (ATAC-seq and H3K27Ac ChIP-seq analysis). Transcriptomics, proteomics, and gene ontology analysis revealed gene changes in cell proliferation, adhesion, migration, and apoptosis. Significantly, HDAC6 inactivation altered P300 ubiquitination, stabilizing P300 and leading to downregulating genes critical for cancer cell survival. Our study highlights the substantial impact of HDAC6 inactivation on the chromatin landscape of cancer cells and suggests a role for P300 in contributing to the anticancer effects. The stabilization of P300 with HDAC6 inhibition proposes a potential shift in therapeutic focus from HDAC6 itself to its interaction with P300. This finding opens new avenues for developing targeted cancer therapies, improving our understanding of epigenetic mechanisms in cancer cells.
2024-08-19 | GSE273644 | GEO