Mitotic H3K9 acetylation patterns are controlled by phase-specific activity of the histone deacetylases HDAC2, 3 and SIRT1
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ABSTRACT:
PROVIDER: PRJNA706406 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13849316_1.fastq.gz | Fastqsanger.gz | |||
| SRR13849316_2.fastq.gz | Fastqsanger.gz | |||
| SRR13849317_1.fastq.gz | Fastqsanger.gz | |||
| SRR13849317_2.fastq.gz | Fastqsanger.gz | |||
| SRR13849318_1.fastq.gz | Fastqsanger.gz |
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Project description:Histone acetylation play a fundamental role in many biological processes. H3K9ac is tightly linked to active transcription, and enriched in promoters, enhancers and insulators. During mitosis H3k9ac levels are reduced, and the mechanism of this reduction is not clear. Here, we used small molecules inhibitors of histone deacetylases and evaluated by immunofluorescence and western blots the involvement of each of the targeted enzymes in regulating H3K9ac during prophase, metaphase, anaphase, telophase and cytokinesis. We identified three histone deacetylases, HDAC2, HDAC3 and SIRT1, as modulators of H3K9ac mitotic levels. HDAC2 inhibition, increased global H3K9ac in prophase, whereas HDAC3 or SIRT1 inhibition, increased H3K9ac levels in metaphase. Next, we performed ChIP-seq in mitotic cells following specific inhibition of each of these histone deacetylases. While we observed a high concordance between the genomic areas impacted by HDAC2 and HDAC3, we detected a small set of loci that were unique to each condition, with HDAC3-specific targets being enriched for genes involved in mitosis regulation.
2022-08-14 | GSE168180 | GEO
Project description:We report the genome-wide accumulation of HDAC1, HDAC2 and H3K9/14Ac in B cells. We found that the binding of HDAC1 and HDAC2 was observed mainly on proximal promoters, suggesting a redundant role of these HDACs in transcriptional regulation. This study provides a basis for the comprehensive understanding of Tet2/Tet3-HDACs-mediated B cell regulation.
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Project description:SALL4 builds a complex with histone deacetylases, and is thought to confer its effects epigenetically. Both loss of Sall4 and inhibition of HDAC2 leads to an invasiveness in human melanoma cells. To study co-occupancy of SALL4 and HDAC2, we employed CUT&RUN targeting SALL4 and HDAC2 in human melanoma cells (M010817).
2021-06-30 | E-MTAB-10163 | biostudies-arrayexpress
Project description:The deacetylases HDAC1/HDAC2 control JAK2V617F-STAT signaling through the ubiquitin ligase SIAH2
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Project description:Histone deacetylases (HDACs) have been widely pursued as targets for anti-cancer therapeutics. However, many of these targets are universally essential for cell survival, which may limit the therapeutic window that can be achieved by drug candidates. By examining large collections of CRISPR/Cas9-based essentiality screens, we discovered a genetic interaction between HDAC1 and HDAC2 wherein each paralog is synthetically lethal with hemizygous deletion of the other. This collateral synthetic lethality is caused by recurrent chromosomal translocations that occur in diverse solid and hematological malignancies, including neuroblastoma and multiple myeloma. Using genetic deletion or dTAG-mediated degradation, we show that HDAC2 disruption suppresses the growth of HDAC1-deficient neuroblastoma in vitro and in vivo. Mechanistically, we find that targeted degradation of HDAC2 in these cells prompts the degradation of several members of the nucleosome remodeling and deacetylase (NuRD) complex, leading to diminished chromatin accessibility at HDAC2/NuRD-bound sites of the genome and impaired control of enhancer-associated transcription. Furthermore, we reveal that several of the degraded NuRD complex subunits are dependencies in neuroblastoma and multiple myeloma, providing motivation to develop paralog-selective HDAC1 or HDAC2 degraders. Altogether, we identify HDAC1/2 collateral synthetic lethality as a new therapeutic target and reveal a novel mechanism for exploiting NuRD-associated cancer dependencies.
2023-06-11 | PXD034444 | Pride
Project description:Recent studies have shown that repressive chromatin machinery, including DNA methyltransferases (DNMTs) and Polycomb Repressor Complexes (PRCs), bind to chromosomes throughout mitosis and their depletion results in increased chromosome size. Enzymes that catalyse H3K9 methylation, such as Suv39h1, Suv39h2, G9a, GLP are also retained by mitotic chromosomes. Surprisingly however, mutants lacking H3K9me3 have unusually small and compact mitotic chromosomes that are associated with increased H3S10ph and H3K27me3 levels. Chromosome size and centromere compaction in these mutants was rescued by providing exogenous Suv39h1, or inhibiting Ezh2 activity. Quantitative proteomic comparisons of native mitotic chromosomes isolated from wildtype versus Suv39h1,2 double null ESCs revealed that H3K9me3 was essential for the efficient retention of bookmarking factors such as Esrrb. These results highlight an unexpected role for repressive heterochromatin domains in preserving transcription factor binding through mitosis, and underscore the importance of H3K9me3 for sustaining chromosome architecture and epigenetic memory during cell division.
2022-10-12 | PXD030771 | Pride
Project description:Class I histone deacetylases HDAC1 and HDAC2 contribute to cell proliferation and are commonly upregulated in urothelial carcinoma (UC). To evaluate whether specific inhibition of HDAC1 and HDAC2 might serve as an appropriate therapy of UC we applied specific siRNA mediated double knockdown of HDAC1 and HDAC2 in the UCCs VM-CUB1 and UM-UC-3. HDAC1/2 double knockdown significantly reduced proliferation and clonogenicity of UC cells.
2016-01-31 | GSE74477 | GEO
Project description:Epigenetic modulators of the histone deacetylase (HDAC) family control key biological processes and are frequently dysregulated in cancer. There is superior activity of HDAC inhibitors (HDACi) in patients with myeloproliferative neoplasms (MPNs) that carry the Janus kinase-2 point mutant JAK2V617F. This constitutively active tyrosine kinase activates signal-transducer-and-activator-of-transcription (STAT) transcription factors to promote cell proliferation and inflammatory processes. We reveal that the inhibition of HDAC1/HDAC2 with the clinically advanced HDACi romidepsin, the experimental HDACi entinostat and MERCK60, and genetic depletion of HDAC1/HDAC2 induce apoptosis and long-term growth arrest of primary and permanent MPN cells in vitro and in vivo. This treatment spares normal hematopoietic stem cells and does not compromise blood cell differentiation. At the molecular level, HDAC1 and HDAC2 control the protein stability of SIAH2 through acetylation. Genetic knockout experiments show that SIAH2 accelerates the proteasomal degradation of JAK2V617F in conjunction with the E2 ubiquitin-conjugating enzyme UBCH8. SIAH2 binds to the surface-exposed SIAH degron motif VLP1002 in the catalytic domain of JAK2V617F. At the functional level, SIAH2 knockout MPN cells are significantly less sensitive to HDACi. Global RNA sequencing verifies that JAK-STAT signaling is a prime target of SIAH2. Moreover, HDAC1 is an adverse prognostic factor in patients with acute myeloid leukemia (n = 150, p = 0.02), being a possible complication of MPNs. These insights reveal a previously unappreciated link between HDAC1/HDAC2 as key molecular targets, the still undefined regulation of cytoplasmic-to-nuclear signaling by HDACs, and how HDACi kill JAK2V617F-positive cells from MPN patients and mice with JAK2V617F in vitro and in vivo.
2025-08-04 | GSE243648 | GEO
Project description:The aim of our study is to determine the functions of histone deacetylases (HDACs) 1 and 2 in Schwann cells during postnatal development of the peripheral nervous system (PNS). Schwann cells are the myelinating glial cells of the PNS. At birth, mouse sciatic nerves mature in 2 subsequent phases: 1/ big caliber axons get sorted into a 1 to 1 relationship with Schwann cells, 2/ Schwann cells build a myelin sheath around sorted axons. In mice where both HDAC1 & HDAC2 have been specifically knocked out in Schwann cells, both phases are impaired. HDACs are chromatin remodeling enzymes, they can thus alter gene expression directly. We want to identify which genes controlled by HDAC1 and HDAC2 in Schwann cells are necessary for the maturation of sciatic nerves. Because HDAC1 and HDAC2 can compensate for each other loss to some extend, we will first analyze changes of gene expression in HDAC1/HDAC2 double KO animals. We expect to gain critical insights into the molecular mechanisms controlling Schwann cell differentiation and myelination. This knowledge is of key importance for the success of regenerative medicine in peripheral neuropathies, nerve tumors, and transplantation paradigms in non-regenerative CNS lesions and in large PNS injuries. 3 double knockout mutants for HDAC1 and HDAC2 and 3 control littermates were analyzed. Tissues analyzed: sciatic nerves of 2 day-old mouse pups
2011-02-25 | E-GEOD-27451 | biostudies-arrayexpress
Project description:Acetylation and deacetylation of histones and other proteins depend on the opposing activities of histone acetyltransferases and histone deacetylases (HDACs), leading to either positive or negative gene expression changes. The use of HDAC inhibitors (HDACi) has uncovered a role for HDACs in the control of proliferation, apoptosis and inflammation. However, little is known of the roles of specific HDACs in intestinal epithelial cells (IEC). We investigated the consequences of ablating both Hdac1 and Hdac2 in murine IECs gene expression. HDAC1 and HDAC2 conditionally mutated mice were provided by Dr EN Olson (University of Texas Southwestern Medical Center, Dallas, TX) (Montgomery et al., 2007). Floxed HDAC1 and HDAC2 mice were crossed with villin-Cre transgenic mice to insure specific intestinal epithelial cell gene deletion (Madison et al., 2002). Total RNAs from the colon of three control and three HDAC1/2 IEC-specific knockout mice were isolated with the Rneasy kit (Qiagen, Mississauga, ON, Canada).
2013-06-08 | E-GEOD-47745 | biostudies-arrayexpress