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Oncohistone mutations occur at functional sites of regulatory ADP-ribosylation: the role of oncohistone mutations in transcriptional regulation [RNA-Seq]

ABSTRACT: RNA-seq were performed in MDA-MB-231 cells ectopically expressing FLAG-tagged WT, D51A, or D51N H2B, and WT, D68A, or D68N H4

ORGANISM(S): Homo sapiens

PROVIDER: GSE180461 | GEO | 2022/08/02

REPOSITORIES: GEO

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Oncohistone mutations occur at functional sites of regulatory ADP-ribosylation: the role of oncohistone mutations in transcriptional regulation [ATAC-Seq]

Project description:ATAC-seq were performed in MDA-MB-231 cells ectopically expressing FLAG-tagged WT, D51A, or D51N H2B, and WT, D68A, or D68N H4

2022-08-02 | GSE180458 | GEO

Oncohistone mutations occur at functional sites of regulatory ADP-ribosylation: the role of oncohistone mutations in transcriptional regulation [ChIP-Seq]

Project description:H2BK12ac ChIP-seq were performed in MDA-MB-231 cells ectopically expressing FLAG-tagged WT, D51A, or D51N H2B ± treatment with A485 (5 M, 2 hours) or vehicle (DMSO).

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Oncohistone mutations occur at functional sites of regulatory ADP-ribosylation: the role of oncohistone mutations in transcriptional regulation

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-08-02 | GSE180463 | GEO

Inhibition of Histone H3-H4 Chaperone Pathways Rescues Dysfunctional Oncohistone H2B

Project description:Oncohistone mutations are crucial drivers for tumorigenesis, but how a living organism responds to and governs the loss-of-function oncohistone remains unclear. Here, we generated a histone H2B triple knockout (3KO) strain in Caenorhabditis elegans, which decreased the embryonic H2B level, disrupted cell divisions, and caused animal sterility. Our genetic screens identified mutations defective in a histone H3-H4 chaperone UNC-85 as suppressors that recovered H2B 3KO fertility. We found that unc-85 mutations reduced chromatin H3-H4 levels and that inhibiting other H3-H4 chaperones or H3-H4 histones also rescued H2B 3KO sterility. The oncohistone H2BE76K mutation disrupts the H2B-H4 interface and causes nucleosome instability, and we showed that blocking H3-H4 chaperones restored cell division defects in C. elegans or human cells carrying H2BE76K. Thus, our results indicate that reducing chromatin H3-H4 rescues H2B loss and suggest that inhibiting H3-H4 chaperones may be a therapeutic strategy to treat cancers resulting from loss-of-function H2B oncohistone.

2022-04-03 | GSE185582 | GEO

Functional Interplay between Histone H2B ADP-Ribosylation and Phosphorylation Controls Adipogenesis

Project description:Although ADP-ribosylation of histones by PARP-1 has been linked to genotoxic stress responses, its role in physiological processes has remained elusive. We found that ADPribosylation of histone H2B-Glu35 inhibits the differentiation of adipocyte precursors, leading to a reduction of newly formed adipocytes in white adipose tissue. ADP-ribosylation of Glu35 by PARP-1 inhibits phosphorylation of adjacent H2B-Ser36, which is required for the proadipogenic gene expression program. It also inhibits adipogenesis in cultured cells and a mouse lineage tracing genetic model. The activity of PARP-1 on H2B requires NMNAT-1, a nuclear NAD+ synthase, which serves as a specificity factor to direct PARP-1 catalytic activity to Glu and Asp residues. Collectively, our results demonstrate a functional interplay between H2B-Glu35 ADP-ribosylation and H2B-Ser36 phosphorylation that controls adipogenesis and cancer cell proliferation.

2020-08-13 | GSE136055 | GEO

The H2BE76K mutation drives breast cancer development by enhancing the transcription of ADAM19

Project description:Study was conducted to understand the effect of the cancer associated H2BE76K mutation. Using CRISPR/Cas9 Knock-in cell lines expressing FLAG-tagged WT and E76K mutant H2B, we conducted gene expression profiling experiments and studied the effect of the H2BE76K mutation on H2B occupancy using CUT&RUN sequencing.

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ADP-ribosylation of arginine.

Project description:Arginine adenosine-5'-diphosphoribosylation (ADP-ribosylation) is an enzyme-catalyzed, potentially reversible posttranslational modification, in which the ADP-ribose moiety is transferred from NAD(+) to the guanidino moiety of arginine. At 540 Da, ADP-ribose has the size of approximately five amino acid residues. In contrast to arginine, which, at neutral pH, is positively charged, ADP-ribose carries two negatively charged phosphate moieties. Arginine ADP-ribosylation, thus, causes a notable change in size and chemical property at the ADP-ribosylation site of the target protein. Often, this causes steric interference of the interaction of the target protein with binding partners, e.g. toxin-catalyzed ADP-ribosylation of actin at R177 sterically blocks actin polymerization. In case of the nucleotide-gated P2X7 ion channel, ADP-ribosylation at R125 in the vicinity of the ligand-binding site causes channel gating. Arginine-specific ADP-ribosyltransferases (ARTs) carry a characteristic R-S-EXE motif that distinguishes these enzymes from structurally related enzymes which catalyze ADP-ribosylation of other amino acid side chains, DNA, or small molecules. Arginine-specific ADP-ribosylation can be inhibited by small molecule arginine analogues such as agmatine or meta-iodobenzylguanidine (MIBG), which themselves can serve as targets for arginine-specific ARTs. ADP-ribosylarginine specific hydrolases (ARHs) can restore target protein function by hydrolytic removal of the entire ADP-ribose moiety. In some cases, ADP-ribosylarginine is processed into secondary posttranslational modifications, e.g. phosphoribosylarginine or ornithine. This review summarizes current knowledge on arginine-specific ADP-ribosylation, focussing on the methods available for its detection, its biological consequences, and the enzymes responsible for this modification and its reversal, and discusses future perspectives for research in this field.

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Inhibition of Histone H3-H4 Chaperone Pathways Rescues Dysfunctional Oncohistone H2B

Project description:Inhibition of Histone H3-H4 Chaperone Pathways Rescues Dysfunctional Oncohistone H2B

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Poly ADP-ribosylation of SET8 leads to aberrant H4K20 methylation domains in mammalian cells

Project description:In mammalian cells, SET8 mediated Histone H4 Lys 20 monomethylation (H4K20me1) has been implicated in regulating mitotic condensation, DNA replication, DNA damage response, and gene expression. Here we show SET8, the only known enzyme for H4K20me1 is post-translationally poly ADP-ribosylated by PARP1 on lysine residues. PARP1 interacts with SET8 in a cell cycle- dependent manner. Poly ADP-ribosylation on SET8 renders it catalytically compromised and it undergoes degradation via ubiquitylation pathway. Knockdown of PARP1 shifted the relative dynamic equilibrium of H4K20me2 to H4K20me3 in cells. Overexpression or knockdown of PARP1 led to aberrant H4K20me1 domains genome-wide, impacting Wnt signaling pathways genes and transcription factor binding site enrichment. Therefore, SET8 mediated chromatin remodeling in mammalian cells are influenced by poly ADP-ribosylation by PARP1.

2022-11-17 | GSE188744 | GEO

ADP-ribosylation of mitochondrial proteins is mediated by Neuralized-like protein 4 (NEURL4)

Project description:We profiled the transcriptomic changes in Hela N4-KO cells vs. WT cells

2022-01-31 | GSE183952 | GEO