Fine-Tuning Mybl2 Is Required for Proper Mesenchymal-to-Epithelial Transition during Somatic Reprogramming

Carl Ward, Giacomo Volpe, Pierre Cauchy, Anetta Ptasinska, Ruba Almaghrabi, Daniel Blakemore, Monica Nafria, Doris Kestner, Jon Frampton, George Murphy, Yosef Buganim, Keisuke Kaji, Paloma García*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

During somatic reprogramming, Yamanaka's pioneer factors regulate a complex sequence of molecular events leading to the activation of a network of pluripotency factors, ultimately resulting in the acquisition and maintenance of a pluripotent state. Here, we show that, contrary to the pluripotency factors studied so far, overexpression of Mybl2 inhibits somatic reprogramming. Our results demonstrate that Mybl2 levels are crucial to the dynamics of the reprogramming process. Mybl2 overexpression changes chromatin conformation, affecting the accessibility of pioneer factors to the chromatin and promoting accessibility for early immediate response genes known to be reprogramming blockers. These changes in the chromatin landscape ultimately lead to a deregulation of key genes that are important for the mesenchymal-to-epithelial transition. This work defines Mybl2 level as a gatekeeper for the initiation of reprogramming, providing further insights into the tight regulation and required coordination of molecular events that are necessary for changes in cell fate identity during the reprogramming process. Ward et al. show that Mybl2 expression level is a gatekeeper for the initiation of reprogramming. They find that Mybl2 overexpression leads to changes in the chromatin landscape, affecting the accessibility of pioneer factors to the chromatin and promoting accessibility for the AP1 family of transcription factors, known to be reprogramming blockers.

Original languageAmerican English
Pages (from-to)1496-1511.e8
JournalCell Reports
Volume24
Issue number6
DOIs
StatePublished - 7 Aug 2018

Bibliographical note

Publisher Copyright:
© 2018 The Authors

Keywords

  • AP1
  • ATAC-sequencing
  • Jun
  • Sox2
  • chromatin landscape
  • chromatin remodeling
  • induced pluripotent stem cells
  • mesenchymal-to-epithelial transition
  • reprogramming blockers
  • somatic reprogramming

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