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A splicing factor switch controls hematopoietic lineage specification of pluripotent stem cells
Author(s) -
Li Yapu,
Wang Ding,
Wang Hongtao,
Huang Xin,
Wen Yuqi,
Wang BingRui,
Xu Changlu,
Gao Jie,
Liu Jinhua,
Tong Jingyuan,
Wang Mengge,
Su Pei,
Ren Sirui,
Ma Feng,
Li HongDong,
Bresnick Emery H,
Zhou Jiaxi,
Shi Lihong
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202050535
Subject(s) - hematology , medicine , chinese academy of sciences , china , political science , law
Alternative splicing (AS) leads to transcriptome diversity in eukaryotic cells and is one of the key regulators driving cellular differentiation. Although AS is of crucial importance for normal hematopoiesis and hematopoietic malignancies, its role in early hematopoietic development is still largely unknown. Here, by using high‐throughput transcriptomic analyses, we show that pervasive and dynamic AS takes place during hematopoietic development of human pluripotent stem cells (hPSCs). We identify a splicing factor switch that occurs during the differentiation of mesodermal cells to endothelial progenitor cells (EPCs). Perturbation of this switch selectively impairs the emergence of EPCs and hemogenic endothelial progenitor cells (HEPs). Mechanistically, an EPC‐induced alternative spliced isoform of NUMB dictates EPC specification by controlling NOTCH signaling. Furthermore, we demonstrate that the splicing factor SRSF2 regulates splicing of the EPC‐induced NUMB isoform, and the SRSF2‐NUMB‐NOTCH splicing axis regulates EPC generation. The identification of this splicing factor switch provides a new molecular mechanism to control cell fate and lineage specification.