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Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation

ABSTRACT: Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation

PROVIDER: PRJNA448165 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6920790.fastq.gz	Fastqsanger.gz
	SRR6920791.fastq.gz	Fastqsanger.gz
	SRR6920792.fastq.gz	Fastqsanger.gz
	SRR6920793.fastq.gz	Fastqsanger.gz

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Similar Datasets

Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation

Project description:SET domain containing 2 (Setd2), encoding a histone methyltransferase, is associated with many hematopoietic diseases when mutated. By generating a novel exon 6 conditional knockout mouse model, we described an essential role of Setd2 in maintaining the adult hematopoietic stem cells. Loss of Setd2 results in leukopenia, anemia, and increased platelet accompanied with hypocellularity, erythroid dysplasia, and mild fibrosis in bone marrow. Setd2 knockout mice show significantly decreased hematopoietic stem and progenitor cells except for erythroid progenitors. Setd2 knockout hematopoietic stem cells fail to establish long-term bone marrow reconstitution after transplantation, because of the loss of quiescence, increased apoptosis, and reduced multiple-lineage terminal differentiation potential. Bioinformatic analysis revealed that the hematopoietic stem cells exit of quiescence and commit to differentiation, which lead to hematopoietic stem cells exhaustion. Mechanistically, we attribute an important Setd2 function in murine adult hematopoietic stem cells to the inhibition of the Nsd1/2/3 transcriptional complex, which recruits super elongation complex and controls RNA polymerase II elongation on a subset of target genes including Myc. Our results reveal a critical role of Setd2 in regulating quiescence and differentiation of HSCs through restricting the NSDs/SEC mediated RNA Polymerase II elongation.

2018-05-01 | GSE112550 | GEO

<i>Setd2</i> regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation.

Project description:SET domain containing 2 (Setd2), encoding a histone methyltransferase, is associated with many hematopoietic diseases when mutated. By generating a novel exon 6 conditional knockout mouse model, we describe an essential role of Setd2 in maintaining the adult hematopoietic stem cells. Loss of Setd2 results in leukopenia, anemia, and increased platelets accompanied by hypocellularity, erythroid dysplasia, and mild fibrosis in bone marrow. Setd2 knockout mice show significantly decreased hematopoietic stem and progenitor cells except for erythroid progenitors. Setd2 knockout hematopoietic stem cells fail to establish long-term bone marrow reconstitution after transplantation because of the loss of quiescence, increased apoptosis, and reduced multiple-lineage terminal differentiation potential. Bioinformatic analysis revealed that the hematopoietic stem cells exit from quiescence and commit to differentiation, which lead to hematopoietic stem cell exhaustion. Mechanistically, we attribute an important Setd2 function in murine adult hematopoietic stem cells to the inhibition of the Nsd1/2/3 transcriptional complex, which recruits super elongation complex and controls RNA polymerase II elongation on a subset of target genes, including Myc Our results reveal a critical role of Setd2 in regulating quiescence and differentiation of hematopoietic stem cells through restricting the NSDs/SEC mediated RNA polymerase II elongation.

| S-EPMC6029524 | biostudies-literature

Global impact of RNA polymerase II elongation inhibition on alternative splicing regulation

Project description:This SuperSeries is composed of the following subset Series: GSE25287: Global impact of RNA polymerase II elongation inhibition on alternative splicing regulation (expression) GSE25494: Global impact of RNA polymerase II elongation inhibition on alternative splicing regulation (ChIP-Seq) Refer to individual Series

2010-12-09 | E-GEOD-25495 | biostudies-arrayexpress

setd2 knockout zebrafish is survivable and fertile: differential and developmental-stress-related requirements for Setd2 and histone H3K36 trimethylation in different vertebrate animals

Project description:Setd2 is the only enzyme that catalyzes histone H3 lysine 36 trimethylation (H3K36me3) on virtually all actively transcribed protein-coding genes, and this mechanism is evolutionarily conserved from yeast to human. Setd2 and H3K36me3 have been revealed to be involved in many important biochemical mechanisms, including DNA repair, alternative mRNA splicing and transcription elongation. However, physiological function of Setd2 in the context of zebrafish development remains elusive. Here we generated zebrafish setd2 mutant lines through disrupting the majority of the protein. And mRNA profiles of wild-type (WT), Setd2(+/-) and Setd2(-/-) zebrafish embryos at 36hpf were generated by deep sequencing, providing an opportunity to uncover molecular programs and functions of Setd2.

2020-05-27 | GSE151238 | GEO

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

Project description:Signal-dependent RNA Polymerase II (Pol2) productive elongation is an integral component of gene transcription, including those of immediate early genes (IEGs) induced by neuronal activity. However, it remains unclear how productively elongating Pol2 overcome nucleosomal barriers. Using RNAi, three degraders, and several small molecule inhibitors, we show that the mammalian SWI/SNF complex of neurons (neuronal BAF, or nBAF) is required for activity-induced transcription of neuronal IEGs, including Arc. The nBAF complex facilitates promoter-proximal Pol2 pausing, signal-dependent Pol2 recruitment (loading), and importantly, mediates productive elongation in the gene body via interaction with the elongation complex and elongation-competent Pol2. Mechanistically, Pol2 elongation is mediated by activity-induced nBAF assembly (especially, ARID1A recruitment) and its ATPase activity. Together, our data demonstrate that the nBAF complex regulates several aspects of Pol2 transcription and reveal mechanisms underlying activity-induced Pol2 elongation. These findings may offer insights into human maladies etiologically associated with mutational interdiction of BAF functions.

2024-06-18 | PXD052840 | JPOST Repository

Molecular Determinants for RNA Polymerase II Elongation Rate and Acceleration

Project description:Recent studies reveal a striking phenomenon that RNA Polymerase II (Pol II) appears to travel on gene body in an accelerated fashion, but the mechanism has remained unknown. We performed synchronized transcription coupled with deep sequencing, observing an inverse relationship between initial rate and acceleration in different cell types. We directly tested several correlative events and detected a positive contribution of the splicing commitment factor SRSF2 to Pol II acceleration, suggesting a functional benefit of co-transcriptional pre-mRNA splicing in transcription elongation. Unexpectedly, we found that perturbation of Pol II Ser2 phosphorylation had little impact on Pol II elongation or acceleration. While H3K79me2 has been positively correlated with Pol II elongation, we showed that reduction of this histone modification event actually accelerated Pol II elongation. Together, these data suggest a combined effect of gradual gain-of-competence and gradual lost-of-epigenetic barriers as the mechanism for accelerated Pol II elongation. DRB time-course releasing assay under functional perturbation

2015-12-31 | E-GEOD-66021 | biostudies-arrayexpress

Elongation factor-specific capture of RNA polymerase II complexes

Project description:Elongation factor-specific capture of RNA polymerase II complexes

| PRJNA856248 | ENA

MDC1 maintains active elongation complexes of RNA polymerase II

Project description:MDC1 maintains active elongation complexes of RNA polymerase II

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Role of Setd2 in regulatory T cells

Project description:This SuperSeries is composed of the SubSeries listed below. To determine the molecular regulation of Tregs by Setd2, Spleen or large intestine Tregs (CD3+CD4+Foxp3-YFP+) were purified from littermate Foxp3Cre-YFPSetd2f/+ and Foxp3Cre-YFPSetd2f/f mice. Setd2-deficient and control Tregs were subjected to RNA-seq, RNA Polymerase II CUT&Tag or H3K27ac CUT&Tag analyses.

2022-10-14 | GSE182845 | GEO

NDF Is a Transcription Factor that Stimulates Elongation by RNA Polymerase II

Project description:RNA polymerase II (Pol II) elongation is a critical step in gene expression. Here we find that NDF, which was identified as a bilaterian nucleosome-destabilizing factor, is also a Pol II transcription factor that stimulates elongation with plain DNA templates in the absence of nucleosomes. NDF binds directly to Pol II and enhances elongation by a different mechanism than does transcription factor TFIIS. Moreover, yeast Pdp3, which is related to NDF, binds to Pol II and stimulates elongation. Thus, NDF is a Pol II-binding transcription elongation factor that is localized over gene bodies and is conserved from yeast to humans.

2022-03-10 | GSE185464 | GEO

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