SRRM2 splicing factor modulates cell fate in early development

Author:

Carvalho Silvia123456ORCID,Zea-Redondo Luna17ORCID,Tang Tsz Ching Chloe1ORCID,Stachel-Braum Philipp789ORCID,Miller Duncan1011ORCID,Caldas Paulo234ORCID,Kukalev Alexander1ORCID,Diecke Sebastian1011ORCID,Grosswendt Stefanie89ORCID,Grosso Ana Rita234ORCID,Pombo Ana17ORCID

Affiliation:

1. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Epigenetic Regulation and Chromatin Structure Group 1 , 10115 Berlin , Germany

2. NOVA School of Science and Technology, Universidade NOVA de Lisboa 2 Associate Laboratory i4HB – Institute for Health and Bioeconomy , , 2829-516 Caparica , Portugal

3. NOVA School of Science and Technology 3 UCIBIO – Applied Molecular Biosciences Unit, Department of Life Sciences , , , 2829-516 Caparica , Portugal

4. Universidade NOVA de Lisboa 3 UCIBIO – Applied Molecular Biosciences Unit, Department of Life Sciences , , , 2829-516 Caparica , Portugal

5. Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto 4 , 4050-313 Porto , Portugal

6. ICBAS, University of Porto 5 Graduate Program in Areas of Basic and Applied Biology (GABBA) , , 4050-313 Porto , Portugal

7. Institute of Biology 6 Humboldt-Universität zu Berlin , , 10115 Berlin , Germany

8. Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin 7 , Exploratory Diagnostic Sciences (EDS) 10178 Berlin , Germany

9. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), From Cell State to Function Group 8 , 10115 Berlin , Germany

10. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Pluripotent Stem Cells Platform 9 , 13125 Berlin , Germany

11. DZHK (German Centre for Cardiovascular Research), partner site Berlin 10 , 10785 Berlin , Germany

Abstract

ABSTRACT 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.

Funder

Fundação para a Ciência e Tecnologia

Deutsche Forschungsgemeinschaft

HORIZON EUROPE Marie Sklodowska-Curie Actions

Helmholtz Association

Publisher

The Company of Biologists

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3