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 3 alpha (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.

DNMT3A-coordinated splicing governs the stem state switch towards differentiation in embryonic and haematopoietic stem cells / Ramabadran, Raghav; Wang, Jarey H; Reyes, Jaime M; Guzman, Anna G; Gupta, Sinjini; Rosas, Carina; Brunetti, Lorenzo; Gundry, Michael C; Tovy, Ayala; Long, Hali; Gu, Tianpeng; Cullen, Sean M; Tyagi, Siddhartha; Rux, Danielle; Kim, Jean J; Kornblau, Steven M; Kyba, Michael; Stossi, Fabio; Rau, Rachel E; Takahashi, Koichi; Westbrook, Thomas F; Goodell, Margaret A. - In: NATURE CELL BIOLOGY. - ISSN 1476-4679. - 25:4(2023), pp. 528-539. [10.1038/s41556-023-01109-9]

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

Brunetti, Lorenzo;
2023-01-01

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 3 alpha (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.
2023
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11566/315569
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 10
  • ???jsp.display-item.citation.isi??? 9
social impact