title: An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming.
abstract: 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.
authors.affiliation: Banting and Best Department of Medical Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Gabut
authors.forename: Payman
authors.initials: P
authors.lastname: Samavarchi-Tehrani
authors.forename: Xinchen
authors.initials: X
authors.lastname: Wang
authors.forename: Valentina
authors.initials: V
authors.lastname: Slobodeniuc
authors.forename: Dave
authors.initials: D
authors.lastname: O'Hanlon
authors.forename: Hoon-Ki
authors.initials: HK
authors.lastname: Sung
authors.forename: Manuel
authors.initials: M
authors.lastname: Alvarez
authors.forename: Shaheynoor
authors.initials: S
authors.lastname: Talukder
authors.forename: Qun
authors.initials: Q
authors.lastname: Pan
authors.forename: Esteban O
authors.initials: EO
authors.lastname: Mazzoni
authors.forename: Stephane
authors.initials: S
authors.lastname: Nedelec
authors.forename: Hynek
authors.initials: H
authors.lastname: Wichterle
authors.forename: Knut
authors.initials: K
authors.lastname: Woltjen
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
authors.forename: Peter W
authors.initials: PW
authors.lastname: Zandstra
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wrana
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D065150:Cellular Reprogramming; D004247:DNA / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D006801:Humans; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; D020033:Protein Isoforms; D012097:Repressor Proteins; D004247:DNA