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

PROVIDER: PRJNA748367 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15197923.fastq.gz	Fastqsanger.gz
	SRR15197924.fastq.gz	Fastqsanger.gz
	SRR15197925.fastq.gz	Fastqsanger.gz
	SRR15197926.fastq.gz	Fastqsanger.gz
	SRR15197927.fastq.gz	Fastqsanger.gz

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

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

| PRJNA748361 | ENA

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

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

| PRJNA748364 | ENA

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

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

| PRJNA748363 | ENA

Oncohistone Mutations Occur at Functional Sites of Regulatory ADP-Ribosylation.

Project description:Recent studies have identified cancer-associated mutations in histone genes that lead to the expression of mutant versions of core histones called oncohistones. Many oncohistone mutations occur at Asp and Glu residues, two amino acids known to be ADP-ribosylated (ADPRylated) by PARP1. We screened 25 Glu or Asp oncohistone mutants for their effects on cell growth in breast and ovarian cancer cells. Ectopic expression of six mutants of three different core histones (H2B, H3, and H4) altered cell growth in at least two different cell lines. Two of these sites, H2B-D51 and H4-D68, were indeed sites of ADPRylation in wild-type (unmutated) histones, and mutation of these sites inhibited ADPRylation. Mutation of H2B-D51 dramatically altered chromatin accessibility at enhancers and promoters, as well as gene expression outcomes, whereas mutation of H4-D68 did not. Additional biochemical, cellular, proteomic, and genomic analyses demonstrated that ADPRylation of H2B-D51 inhibits p300-mediated acetylation of H2B at many Lys residues. In breast cancer cell xenografts in mice, H2B-D51A promoted tumor growth, but did not confer resistance to the cytotoxic effects of PARP inhibition. Collectively, these results demonstrate that functional Asp and Glu ADPRylation sites on histones are mutated in cancers, allowing cancer cells to escape the growth-regulating effects of post-translational modifications via distinct mechanisms.SignificanceThis study identifies cancer-driving mutations in histones as sites of PARP1-mediated ADP-ribosylation in breast and ovarian cancers, providing a molecular pathway by which cancers may subvert the growth-regulating effects of PARP1.

| S-EPMC9256803 | biostudies-literature

Phenotypic and Functional Characterization of Oncohistone Mutations in Breast Cancers [RNA-seq]

Project description:Although mutations in genes encoding histones display a similar prevalence to that of some other somatic mutations in cancer, the underlying mechanisms by which histone mutations drive tumorigenesis have not been fully explored. Herein, we curated missense mutations occurring in core histone genes in breast cancers using data from MSK-IMPACT and cBioPortal to identify high frequency breast cancer-associated histone gene mutations. We characterized 17 high frequency oncohistone mutations in H2A H2B, and H3 that are enriched in breast cancer samples and occurred at glutamate (E), aspartate (D), serine (S), and arginine (R) residues. Many of these mutants co-occur with PIK3CA mutations in breast cancer samples. The oncohistone mutants were expressed in MCF-7 breast cancer cells or MCF10A mammary epithelial cells and screened for effects on oncogenic phenotypes in a variety of cell- and tumor-based assays (i.e., proliferation, migration, invasion, competitive outgrowth, transformation). In addition, we examined the effects of selected mutants on DNA damage, gene expression, and posttranslational modification of histones (e.g., acetylation, phosphorylation, methylation, ADP-ribosylation). Our results indicate that the collection of oncohistone mutants that we screened have varying phenotypic and functional effects. Some can promote cancer-related phenotypes and may act as potential cancer drivers, with H2B-E76K/Q, H3-E97K, and H3-E105K eliciting strong cancer phenotypes. These observations can be used as a resource to connect biological and molecular outcomes to oncohistones in breast cancers.

2025-07-30 | GSE295718 | GEO

Insulin post-transcriptional regulation via PARP12-mediated ADP-ribosylation

Project description:ADP-ribosylation is a common modification that occurs in proteins and nucleic acids, regulating many cellular processes ranging from DNA repair to inflammatory signaling. ADP-ribosylation plays an important role in cancer biology, infectious diseases, and obesity, but its role in the development of type 1 diabetes (T1D) is not well understood. Here, we studied the role of ADP-ribosyltransferase PARP12 in T1D development. PARP12 expression is highly induced in human islets treated with pro-inflammatory cytokines or β cells from diabetic donors. Proteomics analysis of MIN6 insulin-producing cells identified that the RNA machinery is regulated by PARP12 during inflammation. PARP12 also ADP-ribosylates 150 mRNAs, including the insulin mRNA. This mRNA ADP-ribosylation in turn modifies transcript localization and halts translation. Overall, our data identified a role for PARP12 in ADP-ribosylation and translation halting of mRNAs, which may affect insulin production during insulitis.

2025-03-28 | GSE292484 | GEO

Genome-wide analysis of ADP-ribosylation by ADPr-ChAP reveals its association with chromatin after oxidative stress

Project description:Chromatin ADP-ribosylation regulates important cellular processes. However, the exact location and magnitude of chromatin ADP-ribosylation are largely unknown. A robust and versatile method for assessing chromatin ADP-ribosylation is therefore crucial for further understanding its function. Here, we present a chromatin affinity precipitation method based on the high specificity and avidity of two well-characterized ADP-ribose binding domains to map chromatin ADP-ribosylation at the genome-wide scale and at specific loci. Our ADPr-ChAP method revealed that in cells exposed to oxidative stress, ADP-ribosylation of chromatin scaled with histone density, with highest levels at heterochromatic sites and depletion at active promoters. Furthermore, in growth factor-induced adipocyte differentiation, increased chromatin ADP-ribosylation was observed at PPARγ target genes, whose expression is ADP-ribosylation-dependent. In combination with deep-sequencing and conventional ChIP, the established ADPr-ChAP provides a valuable resource for the bioinformatic comparison of ADP-ribosylation with other chromatin modifications and for addressing its role in other biologically important processes.

2016-02-04 | GSE69885 | GEO

ADP-ribosylation of STAT1α by PARP-1 is Required for IFNγ-stimulated Transcriptional Responses in Macrophages [iBMDM_Stat1_mutant_RNAseq]

Project description:A key determinant of the pro-inflammatory responses in macrophages is the Signal Transducers and Activators of Transcription (STAT) family member, STAT1α. STAT1α activation by interferon-gamma (IFNγ) leads to induction of a transcriptional program that is coordinated in a large part by post-translational modifications such as phosphorylation. Poly(ADP-ribose) Polymerases (PARPs), which include PARP-1, catalyze the addition of ADP-ribose moieties (ADP-ribosylation) to target proteins and modulate their function. We found that PARP-1 mediates IFNγ-stimulated transcription by regulating genome-wide binding of STAT1α and its IFNγ-dependent phosphorylation. We identified STAT1α as a target of PARP-1 and found sites of ADP-ribosylation on its DNA-binding (DBD) and Transcription Activation (TA) domains. Surprisingly, ADP-ribosylation on the DBD and TA domains had distinct functional consequences on STAT1α transcriptional activity. Moreover, loss of ADP-ribosylation on either site led to diminished pro-inflammatory responses. These results suggest that PARP-1-driven ADP-ribosylation of STAT1α is a critical mediator of inflammation in macrophages.

2021-05-13 | GSE147959 | 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

Epigenetic control of replication, gene expression and growth phase by ADP-ribosylation of DNA in Mycobacterium tuberculosis [RNAseq_LogStationary]

Project description:Mycobacterium tuberculosis maintains long-term infections characterised by the need to regulate growth and adapt to contrasting in vivo environments. Here we show that M. tuberculosis complex bacteria utilise reversible ADP-ribosylation of single-stranded DNA as an epigenetic mechanism to coordinate stationary phase growth with transcriptional adaptation. The DNA-modification is controlled by DarT, an ADP-ribosyl transferase, which adds ADP-ribose to thymidine, and DarG, which enzymatically removes this base modification. Using darG-knockdown M. bovis BCG, we map the first DNA-ADP-ribosylome from any organism. We show that inhibition of replication by DarT is reversible and accompanied by extensive ADP-ribosylation at the origin of replication (OriC). In addition, we observe ADP-ribosylation across the genome and demonstrate that ADP-ribose-thymidine alters the transcriptional activity of M. tuberculosis RNA polymerase. Furthermore, we demonstrate that during stationary phase, DarT-dependent ADP-ribosylation of M. tuberculosis DNA is required to optimally induce expression of the Zur regulon including the ESX-3 secretion system and multiple alternative ribosome proteins. Thus, ADP-ribosylation of DNA can provide an epigenetic link through every aspect of DNA biology from replication to transcription to translation.

2025-02-26 | GSE283124 | GEO

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