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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE222906 | GEO | 2023/01/16

REPOSITORIES: GEO

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DNMT3A-coordinated splicing governs the stem state switch towards differentiation in embryonic and haematopoietic stem cells.

Project description:Upon stimulation by extrinsic stimuli, stem cells initiate a programme 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 that this switch involves a global increase in splicing efficiency coordinated by DNA methyltransferase 3α (DNMT3A), an enzyme typically involved in DNA methylation. Proper activation of murine and human embryonic and haematopoietic stem cells depends on messenger RNA 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 leukaemias. Together, our results reveal a modality through which DNMT3A and the spliceosome govern exit from the stem state towards differentiation.

| S-EPMC10337578 | biostudies-literature

DNMT3A-coordinated splicing governs the stem state switch toward differentiation in embryonic and hematopoietic stem cells [RNA-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 | GSE222905 | GEO

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

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 [RNA-seq]

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

| PRJNA923814 | 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]

| PRJNA923815 | ENA

A splicing factor switch controls hematopoietic lineage specification of pluripotent stem cells

Project description:Alternative splicing (AS) leads to transcriptome diversity in eukaryotic cells and is one of the key regulators driving cellular differentiation. Although AS is of crucial importance for normal hematopoiesis and hematopoietic malignancies, its role in early hematopoietic development is still largely unknown. Here, by using high-throughput transcriptomic analyses, we show that pervasive and dynamic AS takes place during hematopoietic development of human pluripotent stem cells (hPSCs). We identify a splicing factor switch that occurs during the differentiation of mesodermal cells to endothelial progenitor cells (EPCs). Perturbation of this switch selectively impairs the emergence of EPCs and hemogenic endothelial progenitor cells (HEPs). Mechanistically, an EPC-induced alternative spliced isoform of NUMB dictates EPC specification by precisely controlling NOTCH signaling. Furthermore, we demonstrate that the splicing factor SRSF2 regulates splicing of the EPC-induced NUMB isoform, and the SRSF2-NUMB-NOTCH splicing axis regulates EPC generation. The identification of this splicing factor switch provides a new molecular mechanism to control cell-fate and lineage specification.

| S-SCDT-EMBOR-2020-50535V1 | biostudies-other

A splicing factor switch controls hematopoietic lineage specification of pluripotent stem cells.

Project description:Alternative splicing (AS) leads to transcriptome diversity in eukaryotic cells and is one of the key regulators driving cellular differentiation. Although AS is of crucial importance for normal hematopoiesis and hematopoietic malignancies, its role in early hematopoietic development is still largely unknown. Here, by using high-throughput transcriptomic analyses, we show that pervasive and dynamic AS takes place during hematopoietic development of human pluripotent stem cells (hPSCs). We identify a splicing factor switch that occurs during the differentiation of mesodermal cells to endothelial progenitor cells (EPCs). Perturbation of this switch selectively impairs the emergence of EPCs and hemogenic endothelial progenitor cells (HEPs). Mechanistically, an EPC-induced alternative spliced isoform of NUMB dictates EPC specification by controlling NOTCH signaling. Furthermore, we demonstrate that the splicing factor SRSF2 regulates splicing of the EPC-induced NUMB isoform, and the SRSF2-NUMB-NOTCH splicing axis regulates EPC generation. The identification of this splicing factor switch provides a new molecular mechanism to control cell fate and lineage specification.

| S-EPMC7788460 | biostudies-literature

Dnmt3a is essential for hematopoietic stem cell differentiation.

Project description:Loss of the de novo DNA methyltransferases Dnmt3a and Dnmt3b in embryonic stem cells obstructs differentiation; however, the role of these enzymes in somatic stem cells is largely unknown. Using conditional ablation, we show that Dnmt3a loss progressively impairs hematopoietic stem cell (HSC) differentiation over serial transplantation, while simultaneously expanding HSC numbers in the bone marrow. Dnmt3a-null HSCs show both increased and decreased methylation at distinct loci, including substantial CpG island hypermethylation. Dnmt3a-null HSCs upregulate HSC multipotency genes and downregulate differentiation factors, and their progeny exhibit global hypomethylation and incomplete repression of HSC-specific genes. These data establish Dnmt3a as a critical participant in the epigenetic silencing of HSC regulatory genes, thereby enabling efficient differentiation.

| S-EPMC3637952 | biostudies-literature

Loss of Dnmt3a Immortalizes Hematopoietic Stem Cells In Vivo.

Project description:Somatic mutations in DNMT3A are recurrent events across a range of blood cancers. Dnmt3a loss of function in hematopoietic stem cells (HSCs) skews divisions toward self-renewal at the expense of differentiation. Moreover, DNMT3A mutations can be detected in the blood of aging individuals, indicating that mutant cells outcompete normal HSCs over time. It is important to understand how these mutations provide a competitive advantage to HSCs. Here we show that Dnmt3a-null HSCs can regenerate over at least 12 transplant generations in mice, far exceeding the lifespan of normal HSCs. Molecular characterization reveals that this in vivo immortalization is associated with gradual and focal losses of DNA methylation at key regulatory regions associated with self-renewal genes, producing a highly stereotypical HSC phenotype in which epigenetic features are further buttressed. These findings lend insight into the preponderance of DNMT3A mutations in clonal hematopoiesis and the persistence of mutant clones after chemotherapy.

| S-EPMC5908249 | biostudies-literature

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