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
Affiliations
Carl Ward
Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Giacomo Volpe
Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Pierre Cauchy
Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Department of Molecular and Cellular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
Anetta Ptasinska
Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Ruba Almaghrabi
Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Daniel Blakemore
Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Monica Nafria
Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Doris Kestner
Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Jon Frampton
Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
George Murphy
Department of Medicine, Boston University School of Medicine, Boston, MA, USA
Yosef Buganim
The Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel
Keisuke Kaji
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
Paloma García
Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; Corresponding author
Summary: 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. Keywords: somatic reprogramming, mesenchymal-to-epithelial transition, chromatin landscape, ATAC-sequencing, reprogramming blockers, chromatin remodeling, induced pluripotent stem cells, AP1, Sox2, Jun