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DNMT3A-coordinated splicing governs the stem state switch towards differentiation in embryonic and haematopoietic stem cells
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. Ramabadran et al. identify a DNA methylation-independent role for DNMT3A in stem cell activation, mediated through recruitment of SF3B1 and splicing regulation.
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“Both proteins have been associated with additional functions beyond DNA modification.30,31,32,33,34,35,36,37”
From Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging (2024) · cites this paper as [37]
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Metadata
- Authors
- Ramabadran, R., Wang, J. H., Reyes, J. M., Guzman, A. G., Gupta, S., Rosas, C., Brunetti, L., Gundry, M. C., Tovy, A., Long, H., Gu, T., Cullen, S. M., Tyagi, S., Rux, D., Kim, J. J., Kornblau, S. M., Kyba, M., Stossi, F., Rau, R. E., Takahashi, K., Westbrook, T. F., & Goodell, M. A.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2023-04
- Volume
- 25
- Issue
- 4
- Pages
- 528-539
- ISSN
- 1465-7392
- 1476-4679
- PMC
- PMC10337578
- Cited by
- 35
- References
- 56
- Language
- en
- Licence
- www.springernature.com/gp/researchers/text-and-data-mining (tdm)
- www.springernature.com/gp/researchers/text-and-data-mining (vor)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (DK092883, CA183252, AG036695, CA215226, CA186784, CA125123, OD026804)
- United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (1W81XWH1810573)
- Cancer Prevention and Research Institute of Texas (RP160884, RP210227, RP180672)
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (F31DK113705)
- McNair Medical Institute, the Edward P. Evans Foundation, and the American Federation of Aging Research
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