TY - JOUR
T1 - An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming
AU - Gabut, Mathieu
AU - Samavarchi-Tehrani, Payman
AU - Wang, Xinchen
AU - Slobodeniuc, Valentina
AU - O'Hanlon, Dave
AU - Sung, Hoon Ki
AU - Alvarez, Manuel
AU - Talukder, Shaheynoor
AU - Pan, Qun
AU - Mazzoni, Esteban O.
AU - Nedelec, Stephane
AU - Wichterle, Hynek
AU - Woltjen, Knut
AU - Hughes, Timothy R.
AU - Zandstra, Peter W.
AU - Nagy, Andras
AU - Wrana, Jeffrey L.
AU - Blencowe, Benjamin J.
N1 - Funding Information:
B.J.B. dedicates this paper to the memory of S. Levine (1911–2011). We are grateful to D. Schmidt, D. Odom, Q. Morris, N. Barbosa-Morais, S. Mavadadi, and H. van Bakel for advice on data analysis and to A. Golipour for assistance with the iPSC reprogramming experiments. L. Attisano, D. Geschwind, and K.-H. Krause kindly provided valuable reagents, and A. Saltzman, B. Raj, J. Calarco, J. Ellis, H. Han, N. Barbosa-Morais, and M. Q.-Vallières provided helpful comments on the manuscript. Our research was supported by grants from the Canadian Institutes for Health Research (CIHR) to B.J.B., J.L.W., A.N., P.W.Z., and T.R.H., a grant from the Canadian Cancer Society to B.J.B., a grant from Genome Canada (through the Ontario Genomics Institute) to B.J.B. and others, a grant from the Ontario Ministry of Research and Innovation to A.N., and a grant from the Ontario Research Fund to J.L.W., B.J.B., and others. E.O.M., S.N., and H.W. were supported by NIH grant P01 NS055923. E.O.M. is the David and Sylvia Lieb Fellow of the Damon Runyon Cancer Research Foundation (DRG-1937-07). M.G. was supported by postdoctoral fellowships from the C.H. Best Foundation and CIHR. J.L.W. is an International Scholar of the HHMI.
PY - 2011/9/30
Y1 - 2011/9/30
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2011.08.023
DO - 10.1016/j.cell.2011.08.023
M3 - Article
C2 - 21924763
AN - SCOPUS:80052223272
VL - 147
SP - 132
EP - 146
JO - Cell
JF - Cell
SN - 0092-8674
IS - 1
ER -