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

Summary, in English

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.

• Author: Daniel F. Kaemena; Masahito Yoshihara; Meryam Beniazza; James Ashmore; Suling Zhao; Mårten Bertenstam; Victor Olariu; Shintaro Katayama; Keisuke Okita; Simon R. Tomlinson; Kosuke Yusa; Keisuke Kaji
• Department/s: Computational Biology and Biological Physics - Has been reorganised
• Publishing year: 2023-01
• Language: English
• Pages: 488-488
• Publication/Series: Nature Communications
• Volume: 14
• Issue: 1
• Links: http://dx.doi.org/10.1038/s41467-023-36097-9
• Document type: Journal article
• Publisher: Nature Publishing Group
• Topic: Cell and Molecular Biology
• Status: Published
• Project: Computational Science for Health and Environment
• ISBN/ISSN/Other: ISSN: 2041-1723