Abstract

Ectopic expression of lineage master regulators induces transdifferentiation. Whether cell fate transitions can be induced during various developmental stages has not been systemically examined. Here we discover that amongst different developmental stages, mouse embryonic stem cells (mESCs) are resistant to cell fate conversion induced by the melanocyte lineage master regulator MITF. By generating a transgenic system we exhibit that in mESCs, the pluripotency master regulator Oct4, counteracts pro-differentiation induced by Mitf by physical interference with MITF transcriptional activity. We further demonstrate that mESCs must be released from Oct4-maintained pluripotency prior to ectopically induced differentiation. Moreover, Oct4 induction in various differentiated cells represses their lineage identity in vivo. Alongside, chromatin architecture combined with ChIP-seq analysis suggest that Oct4 competes with various lineage master regulators for binding promoters and enhancers. Our analysis reveals pluripotency and transdifferentiation regulatory principles and could open new opportunities in the field of regenerative medicine.

Details

Title
OCT4 impedes cell fate redirection by the melanocyte lineage master regulator MITF in mouse ESCs
Author
Sheinboim, Danna 1 ; Maza, Itay 2 ; Dror, Iris 3 ; Parikh, Shivang 1 ; Krupalnik, Vladislav 4 ; Bell, Rachel E 1 ; Zviran, Asaf 4 ; Suita, Yusuke 5 ; Hakim, Ofir 6 ; Mandel-Gutfreund, Yael 7 ; Mehdi Khaled 8 ; Hanna, Jacob H 4   VIAFID ORCID Logo  ; Levy, Carmit 1 

1  Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 
2  Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel; Department of Gastroenterology, Rambam Health Care Campus & Bruce Rappaport School of Medicine, Technion Institute of Technology, Haifa, Israel 
3  Department of Biology, Technion–Israel Institute of Technology, Haifa, Israel; Department of Biological Chemistry, University of California, Los Angeles, CA, USA 
4  Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel 
5  Cutaneous Biology Research Center, Department of Dermatology and MGH Cancer Center, Massachusetts General Hospital, Boston, MA, USA 
6  The Mina and Everard Goodman Faculty of Life Sciences Bar-Ilan University, Ramat Gan, Israel 
7  Department of Biology, Technion–Israel Institute of Technology, Haifa, Israel 
8  Institut Gustave Roussy, Villejuif, France 
Pages
1-12
Publication year
2017
Publication date
Oct 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-01122-1
ProQuest document ID
1952480028
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.