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Genes Dev. 2015 Apr 15;29(8):803-16. doi: 10.1101/gad.255109.114. Epub 2015 Apr 15.

Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming.

Author information

1
Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
2
Program in Genes and Development, Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
3
Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA; Program in Molecular Carcinogenesis, Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA;
4
Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
5
Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada;
6
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada;
7
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
8
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA; Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
9
Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA;
10
Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
11
Program in Genes and Development, Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA;
12
Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; wrana@lunenfeld.ca sroth@mdanderson.org.
13
Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA; wrana@lunenfeld.ca sroth@mdanderson.org.

Abstract

Embryonic stem cells are maintained in a self-renewing and pluripotent state by multiple regulatory pathways. Pluripotent-specific transcriptional networks are sequentially reactivated as somatic cells reprogram to achieve pluripotency. How epigenetic regulators modulate this process and contribute to somatic cell reprogramming is not clear. Here we performed a functional RNAi screen to identify the earliest epigenetic regulators required for reprogramming. We identified components of the SAGA histone acetyltransferase complex, in particular Gcn5, as critical regulators of reprogramming initiation. Furthermore, we showed in mouse pluripotent stem cells that Gcn5 strongly associates with Myc and that, upon initiation of somatic reprogramming, Gcn5 and Myc form a positive feed-forward loop that activates a distinct alternative splicing network and the early acquisition of pluripotency-associated splicing events. These studies expose a Myc-SAGA pathway that drives expression of an essential alternative splicing regulatory network during somatic cell reprogramming.

KEYWORDS:

Gcn5; Myc; SAGA; alternative splicing; iPSCs; reprogramming

PMID:
25877919
PMCID:
PMC4403257
DOI:
10.1101/gad.255109.114
[Indexed for MEDLINE]
Free PMC Article

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