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hnRNPLL controls pluripotency exit of embryonic stem cells by modulating alternative splicing of Tbx3 and Bptf
Author(s) -
Wang Xue,
Ping Changyun,
Tan Puwen,
Sun Chenguang,
Liu Guang,
Liu Tao,
Yang Shuchun,
Si Yanmin,
Zhao Lijun,
Hu Yongfei,
Jia Yuyan,
Wang Xiaoshuang,
Zhang Meili,
Wang Fang,
Wang Dong,
Yu Jia,
Ma Yanni,
Huang Yue
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020104729
Subject(s) - biology , embryonic stem cell , alternative splicing , rna binding protein , microbiology and biotechnology , rna splicing , cellular differentiation , cell fate determination , stem cell , regulator , transcription factor , regulation of gene expression , gene isoform , genetics , gene , rna
The regulatory circuitry underlying embryonic stem (ES) cell self‐renewal is well defined, but how this circuitry is disintegrated to enable lineage specification is unclear. RNA‐binding proteins (RBPs) have essential roles in RNA‐mediated gene regulation, and preliminary data suggest that they might regulate ES cell fate. By combining bioinformatic analyses with functional screening, we identified seven RBPs played important roles for the exit from pluripotency of ES cells. We characterized hnRNPLL, which mainly functions as a global regulator of alternative splicing in ES cells. Specifically, hnRNPLL promotes multiple ES cell‐preferred exon skipping events during the onset of ES cell differentiation. hnRNPLL depletion thus leads to sustained expression of ES cell‐preferred isoforms, resulting in a differentiation deficiency that causes developmental defects and growth impairment in hnRNPLL ‐KO mice. In particular, hnRNPLL‐mediated alternative splicing of two transcription factors, Bptf and Tbx3 , is important for pluripotency exit. These data uncover the critical role of RBPs in pluripotency exit and suggest the application of targeting RBPs in controlling ES cell fate.