An Alternative Splicing Switch Regulates Embryonic Stem Cell Pluripotency and Reprogramming

• Published in: Cell Vol. 147; no. 1; pp. 132 - 146
• Main Authors: Gabut, Mathieu, Samavarchi-Tehrani, Payman, Wang, Xinchen, Slobodeniuc, Valentina, O'Hanlon, Dave, Sung, Hoon-Ki, Alvarez, Manuel, Talukder, Shaheynoor, Pan, Qun, Mazzoni, Esteban O., Nedelec, Stephane, Wichterle, Hynek, Woltjen, Knut, Hughes, Timothy R., Zandstra, Peter W., Nagy, Andras, Wrana, Jeffrey L., Blencowe, Benjamin J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-09-2011; Elsevier
• Subjects: Alternative Splicing; Animals; Cellular Reprogramming; Differentiation; DNA - metabolism; Embryo cells; embryonic stem cells; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Evolution; Forkhead protein; Forkhead Transcription Factors - metabolism; Foxp1 protein; Gene expression; Gene Expression Regulation, Developmental; genes; Genes, Homeobox; Humans; induced pluripotent stem cells; Life Sciences; Mice; Oct-4 protein; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Protein Isoforms - metabolism; proteomics; Repressor Proteins - metabolism; Somatic cells; Stem cells; transcription (genetics); Transcription factors
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2011.08.023

Alternative splicing (AS) is a key process underlying the expansion of proteomic diversity and the regulation of gene expression. Here, we identify an evolutionarily conserved embryonic stem cell (ESC)-specific AS event that changes the DNA-binding preference of the forkhead family transcription factor FOXP1. We show that the ESC-specific isoform of FOXP1 stimulates the expression of transcription factor genes required for pluripotency, including
OCT4,
NANOG,
NR5A2, and
GDF3, while concomitantly repressing genes required for ESC differentiation. This isoform also promotes the maintenance of ESC pluripotency and contributes to efficient reprogramming of somatic cells into induced pluripotent stem cells. These results reveal a pivotal role for an AS event in the regulation of pluripotency through the control of critical ESC-specific transcriptional programs.
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► An ESC-specific splicing switch in FOXP1 transcripts produces the FOXP1-ES isoform ► FOXP1-ES has distinct DNA-binding properties compared to the canonical FOXP1 isoform ► FOXP1-ES stimulates key pluripotency genes and represses many differentiation genes ► FOXP1-ES is required for ESC pluripotency and efficient iPSC reprogramming
Alternative splicing produces an ESC-specific isoform of FOXP1 that represses genes responsible for differentiation and directly stimulates production of pluripotency genes, including
Oct4 and
Nanog