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

Calley L. Hirsch, Zeynep Coban Akdemir, Li Wang, Gowtham Jayakumaran, Dan Trcka, Alexander Weiss, J. Javier Hernandez, Qun Pan, Hong Han, Xueping Xu, Zheng Xia, Andrew P. Salinger, Marenda Wilson, Frederick Vizeacoumar, Alessandro Datti, Wei Li, Austin J. Cooney, Michelle C. Barton, Benjamin J. Blencowe, Jeffrey L. WranaSharon Y.R. Dent

Research output: Contribution to journalArticle

36 Scopus citations

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. Weidentified components of the SAGA histone acetyltransferase complex, in particular Gcn5, as critical regulators of reprogramming initiation. Furthermore, we showed in mouse pluripotent stemcells 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.

Original languageEnglish (US)
Pages (from-to)803-816
Number of pages14
JournalGenes and Development
Volume29
Issue number8
DOIs
StatePublished - Jan 1 2015

    Fingerprint

Keywords

  • Alternative splicing
  • Gcn5
  • IPSCs
  • Myc
  • Reprogramming
  • SAGA

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Hirsch, C. L., Akdemir, Z. C., Wang, L., Jayakumaran, G., Trcka, D., Weiss, A., Javier Hernandez, J., Pan, Q., Han, H., Xu, X., Xia, Z., Salinger, A. P., Wilson, M., Vizeacoumar, F., Datti, A., Li, W., Cooney, A. J., Barton, M. C., Blencowe, B. J., ... Dent, S. Y. R. (2015). Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming. Genes and Development, 29(8), 803-816. https://doi.org/10.1101/gad.255109.114