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Photo of Victor Olariu

Victor Olariu

Senior lecturer

Photo of Victor Olariu

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

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

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.

Department/s

  • Computational Biology and Biological Physics - Undergoing reorganization

Publishing year

2023-01

Language

English

Pages

488-488

Publication/Series

Nature Communications

Volume

14

Issue

1

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Cell and Molecular Biology

Status

Published

ISBN/ISSN/Other

  • ISSN: 2041-1723