SRRM2 splicing factor modulates cell fate in early development

Embryo development is an orchestrated process that relies on tight regulation of gene expression to guide cell differentiation and fate decisions. The Srrm2 splicing factor has recently been implicated in developmental disorders and diseases, but its role in early mammalian development remains unexplored. Here, we show that Srrm2 dosage is critical for maintaining embryonic stem cell pluripotency and cell identity. Srrm2 heterozygosity promotes loss of stemness, characterised by the coexistence of cells expressing naive and formative pluripotency markers, together with extensive changes in gene expression, including genes regulated by serum-response transcription factor (SRF) and differentiation-related genes. Depletion of Srrm2 by RNA interference in embryonic stem cells shows that the earliest effects of Srrm2 heterozygosity are specific alternative splicing events on a small number of genes, followed by expression changes in metabolism and differentiation-related genes. Our findings unveil molecular and cellular roles of Srrm2 in stemness and lineage commitment, shedding light on the roles of splicing regulators in early embryogenesis, developmental diseases and tumorigenesis.

Descrição

This work was supported by the Helmholtz Association (to A.P., S.G. and S.D.), by the Funda\u00E7ao\u0303 para a Ci\u00EAncia e Tecnologia (PD/BD/135453/2017 and COVID/BD/ 152489/2022 to S.C., UIDP/04378/2020, UIDB/04378/2020, LA/P/0140/2020 to A.R.G.), by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) (International Research Training Group IRTG2403 to A.P. and L.Z.-R.), by the DFG under Germany\u2019s Excellence Strategy (EXC-2049\u2013390688087 to A.P.), by Deutsches Zentrum f\u00FCr Herz-Kreislaufforschung (DZHK), partner site Berlin (Standortprojekt 81Z0100101 to D.M. and to S.D.), by HORIZON EUROPE Marie Sklodowska-Curie Actions (FOX-MTN-HORIZON-MSCA \u2013 2021-PF-01-01 to P.C.). Open Access funding provided by Max-Delbr\u00FCck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft. Deposited in PMC for immediate release. Funding Information: This work was supported by the Helmholtz Association (to A.P., S.G. and S.D.), by the Funda\u00E7a\u00F5 para a Ci\u00EAncia e Tecnologia (PD/BD/135453/2017 and COVID/BD/ 152489/2022 to S.C., UIDP/04378/2020, UIDB/04378/2020, LA/P/0140/2020 to A.R.G.), by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) (International Research Training Group IRTG2403 to A.P. and L.Z.-R.), by the DFG under Germany\u2019s Excellence Strategy (EXC-2049\u2013390688087 to A.P.), by Deutsches Zentrum f\u00FCr Herz-Kreislaufforschung (DZHK), partner site Berlin (Standortprojekt 81Z0100101 to D.M. and to S.D.), by HORIZON EUROPE Marie Sklodowska-Curie Actions (FOX-MTN-HORIZON-MSCA \u2013 2021-PF-01-01 to P.C.). Open Access funding provided by Max-Delbr\u00FCck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft. Deposited in PMC for immediate release. Publisher Copyright: © 2024. Published by The Company of Biologists Ltd.

Palavras-chave

Pluripotency Single-cell transcriptomics Splicing SRm300 Srrm2 Stemness General Biochemistry,Genetics and Molecular Biology General Agricultural and Biological Sciences