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

  1. Sharon Y.R. Dent3,4
  1. 1Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
  2. 2Program in Genes and Development, Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
  3. 3Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
  4. 4Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA;
  5. 5Program in Molecular Carcinogenesis, Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, USA;
  6. 6Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
  7. 7Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada;
  8. 8Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
  9. 9Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA
  1. Corresponding authors: wrana{at}lunenfeld.ca, sroth{at}mdanderson.org
  1. 10 These authors contributed equally to this work.

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

Footnotes

  • Received October 29, 2014.
  • Accepted March 20, 2015.

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