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DNMT3A-coordinated splicing governs the stem state switch toward differentiation in embryonic and hematopoietic stem cells [RNA-seq]

ABSTRACT: Upon stimulation by extrinsic stimuli, stem cells initiate a program that enables differentiation or self-renewal. Disruption of the stem-state exit has catastrophic consequences for embryogenesis and can lead to cancer. While some elements of this stem-state switch are known, major regulatory mechanisms remain unclear. Here, we show this switch involves a global increase in splicing efficiency coordinated by DNMT3A, an enzyme typically involved in DNA methylation. Proper activation of murine and human embryonic and hematopoietic stem cells depends on mRNA processing influenced by DNMT3A in response to stimuli. DNMT3A coordinates splicing through recruitment of the core spliceosome protein SF3B1 to RNA polymerase and mRNA. Importantly, the DNA methylation function of DNMT3A is not required and loss of DNMT3A leads to impaired splicing during stem cell turnover. Finally, we identify the spliceosome as a potential therapeutic target in DNMT3A-mutated leukemias. Together, our results reveal a modality through which DNMT3A and the spliceosome govern exit from the stem-state towards differentiation.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE222905 | GEO | 2023/01/19

REPOSITORIES: GEO

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DNMT3A-coordinated splicing governs the stem state switch toward differentiation in embryonic and hematopoietic stem cells [ChIP-seq]

Project description:Upon stimulation by extrinsic stimuli, stem cells initiate a program that enables differentiation or self-renewal. Disruption of the stem-state exit has catastrophic consequences for embryogenesis and can lead to cancer. While some elements of this stem-state switch are known, major regulatory mechanisms remain unclear. Here, we show this switch involves a global increase in splicing efficiency coordinated by DNMT3A, an enzyme typically involved in DNA methylation. Proper activation of murine and human embryonic and hematopoietic stem cells depends on mRNA processing influenced by DNMT3A in response to stimuli. DNMT3A coordinates splicing through recruitment of the core spliceosome protein SF3B1 to RNA polymerase and mRNA. Importantly, the DNA methylation function of DNMT3A is not required and loss of DNMT3A leads to impaired splicing during stem cell turnover. Finally, we identify the spliceosome as a potential therapeutic target in DNMT3A-mutated leukemias. Together, our results reveal a modality through which DNMT3A and the spliceosome govern exit from the stem-state towards differentiation.

2023-01-19 | GSE222904 | GEO

DNMT3A-coordinated splicing governs the stem state switch toward differentiation in embryonic and hematopoietic stem cells.

Project description:DNMT3A-coordinated splicing governs the stem state switch toward differentiation in embryonic and hematopoietic stem cells.

| PRJNA923811 | ENA

DNMT3A-coordinated splicing governs the stem state switch toward differentiation in embryonic and hematopoietic stem cells [ChIP-seq]

Project description:DNMT3A-coordinated splicing governs the stem state switch toward differentiation in embryonic and hematopoietic stem cells [ChIP-seq]

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DNMT3A-coordinated splicing governs the stem state switch toward differentiation in embryonic and hematopoietic stem cells [RNA-seq]

Project description:DNMT3A-coordinated splicing governs the stem state switch toward differentiation in embryonic and hematopoietic stem cells [RNA-seq]

| PRJNA923814 | ENA

Modeling of the U1 snRNP assembly pathway in alternative splicing in human cells using Petri nets

Project description:The investigation of spliceosomal processes is currently a topic of intense research in molecular biology. In the molecular mechanism of alternative splicing, a multi-protein–RNA complex – the spliceosome – plays a crucial role. To understand the biological processes of alternative splicing, it is essential to comprehend the biogenesis of the spliceosome. In this paper, we propose the first abstract model of the regulatory assembly pathway of the human spliceosomal subunit U1. Using Petri nets, we describe its highly ordered assembly that takes place in a stepwise manner.

2024-10-31 | MODEL2410300001 | BioModels

An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming

Project description:This SuperSeries is composed of the following subset Series: GSE30995: An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming [RNA-Seq] GSE31006: An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming [ChIP-Seq] GSE31007: An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming [protein binding microarray] GSE31948: An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming [AS microarray] Refer to individual Series

2011-09-14 | E-GEOD-30992 | biostudies-arrayexpress

Abnormal RNA splicing and genomic instability after induction of DNMT3A mutations by CRISPR/Cas9 gene editing [RNA-Seq]

Project description:Purpose: DNA methyltransferase 3A (DNMT3A) mediates de novo DNA methylation. Mutations in DNMT3A are associated with hematological malignancies, most frequently acute myeloid leukemia. DNMT3A mutations are hypothesized to establish a pre-leukemic state, rendering cells vulnerable to secondary oncogenic mutations and malignant transformation. However, the mechanisms by which DNMT3A mutations contribute to leukemogenesis are not well-defined. Methods: mRNA profiles of wild-type (WT) and DNMT3A mutated k562 cell lines were generated by deep sequencing, using Illumina HiSeq2500. Sequence reads were trimmed to remove possible adapter sequences and nucleotides with poor quality at the ends. Remaining sequence reads were then aligned to the human reference genome (hg19) using Tophat2. Gene read counts were measured using FeatureCounts and FPKM values were calculated with cufflinks. edgeR was used to identify differentially expressed genes between conditions, and topGO was used for annotation (Alexa, Rahnenfuhrer, and Lengauer, 2006). Sample comparison for differential gene expression was as follows: WTblk and WT1 versus MT2, MT3, MT4, and MT5. Gene enrichment set analysis (GSEA) was conducted with KEGG, Biocarta, and Reactome pathway datasets (Subramanian et al., 2005). Results: DNMT3A-mutated cells displayed impaired differentiation capacity. RNA-seq was used to compare transcriptomes of DNMT3A-mutated and WT cells; DNMT3A ablation resulted in downregulation of genes involved in spliceosome function, causing dysfunction of RNA splicing. Unexpectedly, we observed DNMT3A-mutated cells to exhibit marked genomic instability and an impaired DNA damage response compared to WT. Conclusions: CRISPR/Cas9-mediated DNMT3A-mutated K562 cells may be used to model effects of DNMT3A mutations in human cells. Our findings implicate aberrant splicing and induction of genomic instability as potential mechanisms by which DNMT3A mutations might predispose to malignancy.

2018-01-09 | GSE96634 | GEO

Suppression of prp28-1 splicing defect by prp8-tes allele

Project description:DEAD-box proteins, a family of RNA-dependent ATPases, promote the numerous conformational rearrangements required for spliceosome assembly, activation, and disassembly. Previous work showed that a cold-sensitive substitution in DEAD-box protein Prp28 prevents the switch from U1 to U6 snRNA pairing with the 5’ splice site. Little is known about how Prp28 is regulated, although U5 snRNP protein Prp8 is a potential coordinator of Prp28 and other spliceosomal ATPases. We conducted a targeted selection in Prp8 for cold-insensitive suppressors of prp28-1, then used splicing specific microarrays to assess suppression of the prp28-1 splicing defect. Splicing specific microarrays were used to assess suppression of the prp28-1 splicing defect by a prp8 allele (prp8-tes) that suppresses prp28-1 cold-sensitivity

2014-01-01 | E-GEOD-42754 | biostudies-arrayexpress

The spliceosome factor USP39 promotes hepatocellular carcinoma malignancy through regulating mRNA splicing

Project description:Abnormal alternative splicing (AS) caused by alterations to splicing factors contributes to tumor progression. Nonetheless, the relevant targets and mechanisms remain elusive in hepatocellular carcinoma (HCC). Here, we reported that overexpression of Ubiquitin-specific protease 39 (USP39), a spliceosome component of the U4/U6.U5 tri-snRNP complex, is associated with poor clinical outcomes and proliferative signaling. Functionally, hepatocyte-specific USP39 knockin mice exhibited enhanced hepatocarcinogenesis. In vitro, USP39 promoted HCC cell proliferation and cell cycle progression in a spliceosome-dependent manner. Transcriptomic analysis revealed that USP39 depletion led to comprehensively impaired constitutive splicing and intriguingly, selective AS of hundreds of genes. USP39-mediated splicing switch of KANK2-S to KANK2-L increased the tumorigenic potential of HCC cells through accelerating KANK2 translation. Mechanistically, USP39 modulates exon inclusion/exclusion via interaction with SRSF6 or hnRNPC in a position-dependent manner. These findings highlight a role for USP39 as a splicing regulator in HCC biology and establishing its position-dependent splicing model.

2023-10-24 | PXD035928 | Pride

p38 SAPK and SKIIP induced changes in alternative splicing patterns upon osmostress

Project description:Alternative splicing is a crucial mechanism for gene regulation that is modulated in response to a wide range of extracellular stimuli. Stress-activated protein kinases (SAPKs) play a key role in controlling several steps of mRNA biogenesis. Here, we show that osmostress has a major impact on the regulation of alternative splicing (AS), which is partly mediated through the action of the p38 SAPK. Remarkably, a splicing network analysis revealed a functional connection between p38 and the spliceosome component SKIIP. Depletion of SKIIP abolished a significant part of the p38-mediated alternative splicing.

2019-04-16 | GSE117699 | GEO

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