DNMT3A-Coordinated Splicing Governs the Stem State Switch Towards Differentiation in Embryonic and Haematopoietic Stem Cells

Authors

Raghav Ramabadran
Jarey H Wang
Jaime M Reyes
Anna G Guzman
Sinjini Gupta
Carina Rosas
Lorenzo Brunetti
Michael C Gundry
Ayala Tovy
Hali Long
Tianpeng Gu
Sean M Cullen
Siddhartha Tyagi
Danielle Rux
Jean J Kim
Steven M Kornblau
Michael Kyba
Fabio Stossi
Rachel E Rau
Koichi Takahashi
Thomas F Westbrook
Margaret A Goodell

Publication Date

4-1-2023

Journal

Nature Cell Biology

Abstract

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.

Keywords

Animals, Humans, Mice, Cell Differentiation, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, DNA Methyltransferase 3A, Hematopoietic Stem Cells

Comments

Supplementary Materials

PMID: 37024683