OCT4 impedes cell fate redirection by the melanocyte lineage master regulator MITF in mouse ESCs

Danna Sheinboim, Itay Maza, Iris Dror, Shivang Parikh, Vladislav Krupalnik, Rachel E. Bell, Asaf Zviran, Yusuke Suita, Ofir Hakim, Yael Mandel-Gutfreund, Mehdi Khaled, Jacob H. Hanna () and Carmit Levy ()
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Danna Sheinboim: Tel Aviv University
Itay Maza: Weizmann Institute of Science
Iris Dror: Technion–Israel Institute of Technology
Shivang Parikh: Tel Aviv University
Vladislav Krupalnik: Weizmann Institute of Science
Rachel E. Bell: Tel Aviv University
Asaf Zviran: Weizmann Institute of Science
Yusuke Suita: Massachusetts General Hospital
Ofir Hakim: The Mina and Everard Goodman Faculty of Life Sciences Bar-Ilan University
Yael Mandel-Gutfreund: Technion–Israel Institute of Technology
Mehdi Khaled: Institut Gustave Roussy
Jacob H. Hanna: Weizmann Institute of Science
Carmit Levy: Tel Aviv University

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01122-1

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