B1 SINE-binding ZFP266 impedes mouse iPSC generation through suppression of chromatin opening mediated by reprogramming factors

Daniel F. Kaemena, Masahito Yoshihara, Meryam Beniazza, James Ashmore, Suling Zhao, Mårten Bertenstam, Victor Olariu, Shintaro Katayama, Keisuke Okita, Simon R. Tomlinson, Kosuke Yusa and Keisuke Kaji ()
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Daniel F. Kaemena: University of Edinburgh
Masahito Yoshihara: Karolinska Institutet
Meryam Beniazza: University of Edinburgh
James Ashmore: University of Edinburgh
Suling Zhao: University of Edinburgh
Mårten Bertenstam: Lund University
Victor Olariu: Lund University
Shintaro Katayama: Karolinska Institutet
Keisuke Okita: Kyoto University
Simon R. Tomlinson: University of Edinburgh
Kosuke Yusa: Wellcome Sanger Institute
Keisuke Kaji: University of Edinburgh

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Induced pluripotent stem cell (iPSC) reprogramming is inefficient and understanding the molecular mechanisms underlying this inefficiency holds the key to successfully control cellular identity. Here, we report 24 reprogramming roadblock genes identified by CRISPR/Cas9-mediated genome-wide knockout (KO) screening. Of these, depletion of the predicted KRAB zinc finger protein (KRAB-ZFP) Zfp266 strongly and consistently enhances murine iPSC generation in several reprogramming settings, emerging as the most robust roadblock. We show that ZFP266 binds Short Interspersed Nuclear Elements (SINEs) adjacent to binding sites of pioneering factors, OCT4 (POU5F1), SOX2, and KLF4, and impedes chromatin opening. Replacing the KRAB co-suppressor with co-activator domains converts ZFP266 from an inhibitor to a potent facilitator of iPSC reprogramming. We propose that the SINE-KRAB-ZFP interaction is a critical regulator of chromatin accessibility at regulatory elements required for efficient cellular identity changes. In addition, this work serves as a resource to further illuminate molecular mechanisms hindering reprogramming.

Date: 2023
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DOI: 10.1038/s41467-023-36097-9

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