title: Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming.
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.
authors: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
authors: Calley L
authors: CL
authors: Hirsch
authors: 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;
authors: Zeynep
authors: Z
authors: Coban Akdemir
authors: 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;
authors: Li
authors: L
authors: Wang
authors: 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;
authors: Gowtham
authors: G
authors: Jayakumaran
authors: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
authors: Dan
authors: D
authors: Trcka
authors: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
authors: Alexander
authors: A
authors: Weiss
authors: 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;
authors: J Javier
authors: JJ
authors: Hernandez
authors: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada;
authors: Qun
authors: Q
authors: Pan
authors: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada;
authors: Hong
authors: H
authors: Han
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
authors: Xueping
authors: X
authors: Xu
authors: 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.
authors: Zheng
authors: Z
authors: Xia
authors: 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;
authors: Andrew P
authors: AP
authors: Salinger
authors: Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
authors: Marenda
authors: M
authors: Wilson
authors: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
authors: Frederick
authors: F
authors: Vizeacoumar
authors: Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
authors: Alessandro
authors: A
authors: Datti
authors: 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.
authors: Wei
authors: W
authors: Li
authors: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
authors: Austin J
authors: AJ
authors: Cooney
authors: 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;
authors: Michelle C
authors: MC
authors: Barton
authors: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada;
authors: Benjamin J
authors: BJ
authors: Blencowe
authors: 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.
authors: Jeffrey L
authors: JL
authors: Wrana
authors: 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.
authors: Sharon Y R
authors: SY
authors: Dent
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics*; D053595:Embryonic Stem Cells; D057890:Epigenomics; D018507:Gene Expression Regulation, Developmental; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D039904:Pluripotent Stem Cells; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D051548:Histone Acetyltransferases
keywords: Gcn5; Myc; SAGA; alternative splicing; iPSCs; reprogramming