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HDAC1/2/3 Are Major Histone Desuccinylase Critical for Promoter Desuccinylation [RNA-seq]

ABSTRACT: Lysine succinylation is one of the major post-translational modifications occurred on histones and is believed to have significant roles in regulation of chromatin structure and function. Currently, histone desuccinylation is widely believed to be exerted by the members of SIRT family deacetylases. Here, we report that histone desuccinylation is in fact primarily catalyzed by the class I HDAC1/2/3. Inhibition or depletion of HDAC1/2/3 resulted in marked increase of global histone succinylation, whereas ectopic expression of HDAC1/2/3 but not their deacetylase inactive mutants downregulated global histone succinylation. We demonstrated that the class I HDAC1/2/3 complexes have robust histone desuccinylase activity in vitro. Genomic landscape analysis revealed that histone succinylation is highly enriched at gene promoters and inhibition of HDAC activity results in marked elevation of promoter histone succinylation. Furthermore, integrated analysis revealed that the promoter histone succinylation positively correlates with the transcriptional activity. Collectively, we demonstrate that the class I HDAC1/2/3 but not the SIRT family proteins are the major histone desuccinylases particularly important for promoter histone desuccinylation. Our study thus sheds new light on the role of histone succinylation in transcriptional regulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234005 | GEO | 2023/07/03

REPOSITORIES: GEO

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HDAC1/2/3 Are Major Histone Desuccinylase Critical for Promoter Desuccinylation [ChIP-seq]

Project description:Lysine succinylation is one of the major post-translational modifications occurred on histones and is believed to have significant roles in regulation of chromatin structure and function. Currently, histone desuccinylation is widely believed to be exerted by the members of SIRT family deacetylases. Here, we report that histone desuccinylation is in fact primarily catalyzed by the class I HDAC1/2/3. Inhibition or depletion of HDAC1/2/3 resulted in marked increase of global histone succinylation, whereas ectopic expression of HDAC1/2/3 but not their deacetylase inactive mutants downregulated global histone succinylation. We demonstrated that the class I HDAC1/2/3 complexes have robust histone desuccinylase activity in vitro. Genomic landscape analysis revealed that histone succinylation is highly enriched at gene promoters and inhibition of HDAC activity results in marked elevation of promoter histone succinylation. Furthermore, integrated analysis revealed that the promoter histone succinylation positively correlates with the transcriptional activity. Collectively, we demonstrate that the class I HDAC1/2/3 but not the SIRT family proteins are the major histone desuccinylases particularly important for promoter histone desuccinylation. Our study thus sheds new light on the role of histone succinylation in transcriptional regulation.

2023-07-03 | GSE234004 | GEO

HDAC1/2 and CD4+ T cells

Project description:Dynamic changes in histone acetylation patterns are mediated by the activity of histone acetyltransfereases (HATs) and histone deacetylases (HDACs) and are key events in the epigenetic regulation of gene expression. The application of HDAC inhibitors revealed a variety of T cell functions controlled by reversible lysine acetylation and HDAC1, HDAC2, HDAC3, HDAC7 and HDAC9 have been implicated in regulating T cell development and function. Nevertheless, unique functions of individual HDAC members in T cells and specific T cell functions that are regulated by HDACs are still only poorly understood. We previously showed that T cell-specific loss of HDAC1 (using the Cd4Cre deleter strain) leads to enhanced allergic airway inflammation and increased Th2 cytokine production. Interestingly, late T cell development was not impaired in these mice. However, HDAC2 was up-regulated in the absence of HDAC1, thus we hypothesized compensatory pathways/function between these two closely related class I HDAC family members in T cells. To investigate redundant and non-redundant functions of HDAC1 and HDAC2, we generated mice with a conditional T cell-specific (using Cd4Cre) combined loss of HDAC1 and HDAC2. As part of our study, we determined and compared the transcriptome of peripheral wild-type and HDAC1/2-null CD4+ T cells. Since loss of HDAC1/HDAC2 during late T cell development led to the appearance of MHC class II-selected CD4+ helper T cells that expressed CD8 lineage genes such as Cd8a and Cd8b1, we also analyzed the transcriptome of HDAC1/2-null CD4+CD8+ T cells.

2014-03-30 | E-MTAB-2184 | biostudies-arrayexpress

Transcription profiling of human Burkitts lymphoma cell lines treated with trichostatin A vs controls

Project description:Histone acetylation alters the chromatin state and thus gene expression and cellular activities. In spite of various applications of Histone Deacetylase inhibitors (DACIs) their mechanism or selectivity is not fully understood. We studied the mechanism by which the DACI Trichostatin A upregulates the MHC class II DRA gene in RJ225 cells lacking CIITA. We show that TSA increases HDAC1 and 2 protein mobility and reduces their recruitment to the DRA promoter. Coordinated chromatin changes are manifested by increasing H3 K4 methylation and decreasing K9 methylation, leading to elevated RNA PolII recruitment and the onset of transcription. Gene expression profiling showed that diverse TSA responsive gene groups, including the highly upregulated the MHC class II family and the adjacent histone cluster are located in chromosome 6p21-22. A complex pattern of gene reprogramming by TSA involves immune recognition, antiviral, apoptotic and inflammatory pathways and extends the rationale for using DACIs to modulate the immune response.

2006-08-07 | E-MEXP-403 | biostudies-arrayexpress

Class I histone deacetylases HDAC1, 2 and 3 are histone decrotonylases

Project description:Class I histone deacetylases HDAC1, 2 and 3 are histone decrotonylases

| PRJNA378641 | ENA

Genome-wide maps of histone H3 K79 succinylation in U251 cells.

Project description:We report the nuclear Gcn5/α-KGDH complex plays vital role in histone H3 K79 succinylation. By obtaining over 731 million reads from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of histone H3 K79 succinylation, Gcn5, and α-KGDH in U251 cells.

2017-12-13 | GSE97994 | GEO

RNA-seq analysis of human multiple myeloma cell line RPMI 8226 after HDAC1 knockdown

Project description:Histone deacetylases (HDACs) have emerged as therapeutic targets in multiple myeloma (MM); however, the underlying roles of each class- or isoform-HDAC have not fully clarified. The present study delineates the effect of HDAC1 suppression or inhibition in MM cells. The RNA-seq analysis here revealed that HDAC1 suppression downregulated IRF4 and PIM2, which both play a crucial role in MM cell survival and proliferation. Mechanistically, HDAC1 inhibition dampens IRF4 transcription through histone hyperacetylation and hindrance of RNA polymerase II recruitment at IRF4 locus. PIM2 is transcriptionally under direct regulation by IRF4, thereby reducing PIM2 expression after HDAC1 inhibition. PIM2 is upregulated by the stimuli from bone marrow microenvironment including IL-6 independent of IRF4 regulation in MM cells. Although these stimuli reduce the cytotoxic effect of HDAC1 inhibition in MM cells, direct blockade of PIM2 overcomes the weak point of HDAC1 inhibition. The effect of the combination of class I HDAC inhibitors with PIM inhibitors is further confirmed in vivo mouse xenograft models. Our findings provoke clinical applications of class I HDAC inhibitors in combination with PIM inhibitors against MM.

2022-09-21 | GSE193298 | GEO

Inhibition of class I histone deacetylases 1 and 2 promotes urothelial carcinoma cell death by various mechanisms (HDAC siRNA knockdown)

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

Class I histone deacetylases HDAC1, 2 and 3 are histone decrotonylases

Project description:We characterize histone crotonylation in intestinal epithelium-derived cells through Mass spectrometry, ChIp-Seq and RNA-Seq approaches and show that this modification is removed by class I histone deacetylases, HDAC1, 2 and 3.

2017-12-16 | GSE96035 | GEO

HISTONE DEACETYLASES 1 AND 2 TARGET GENE REGULATORY NETWORKS OF NEPHRON PROGENITORS TO CONTROL NEPHROGENESIS [RNA-seq]

Project description:Our studies demonstrated the critical role of Histone deacetylases (HDACs) in the regulation of nephrogenesis. To better understand the key pathways regulated by HDAC1/2 in early nephrogenesis, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) of Hdac1/2 on isolated nephron progenitor cells (NPCs) from mouse E16.5 kidneys. Our analysis revealed that 11802 (40.4%) of Hdac1 peaks overlap with Hdac2 peaks, further demonstrates the redundant role of Hdac1 and Hdac2 during nephrogenesis. Common Hdac1/2 peaks are densely concentrated close to the transcriptional start site (TSS). GREAT Gene Ontology analysis of overlapping Hdac1/2 peaks reveals that Hdac1/2 are associated with metanephric nephron morphogenesis, chromatin assembly or disassembly, as well as other DNA checkpoints. Pathway analysis shows that negative regulation of Wnt signaling pathway is one of Hdac1/2’s most significant function in NPCs. Known motif analysis indicated that Hdac1 is enriched in motifs for Six2, Hox family, and Tcf family members, which are essential for self-renewal and differentiation of nephron progenitors. Interestingly, we found the enrichment of HDAC1/2 at the enhancer and promoter regions of actively transcribed genes, especially those concerned with NPC self-renewal. Hdac1/2 simultaneously activate or repress the expression of different genes to maintain the cellular state of nephron progenitors. We used the Integrative Genomics Viewer to visualize these target genes associated with each function and found that Hdac1/2 co-bound to the enhancers or/and promoters of genes associated with nephron morphogenesis, differentiation, and cell cycle control. Taken together, our ChIP-Seq analysis demonstrates that Hdac1/2 directly regulate the molecular cascades essential for nephrogenesis.

2022-11-07 | GSE217315 | GEO

Inhibition of class I histone deacetylases 1 and 2 promotes urothelial carcinoma cell death by various mechanisms (HDAC inhibitor treatments)

Project description:Preliminary manuscript abstract: 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 pharmacological inhibition of HDAC1 and HDAC2 with the two selective class I HDAC inhibitors Romidepsin and Givinostat. Treatment with the pan HDAC inhibitor SAHA served as an additional control. Romidepsin and Givinostat significantly reduced proliferation and clonogenicity of UC cells with minor effects on non-tumorigenic cells. Furthermore, compounds induced primarily S-phase disturbances and non-apoptotic cell death. Results of microarray analysis of HDAC inhibitor treated cells match with observed phenotype after pharmacological HDAC1 and HDAC2 inhibition in UC cells.

2016-01-31 | GSE70120 | GEO

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