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

Author

Listed:
  • Daniel F. Kaemena

    (University of Edinburgh)

  • Masahito Yoshihara

    (Karolinska Institutet
    Chiba University
    Chiba University)

  • 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
    University of Helsinki
    Folkhälsan Research Center)

  • Keisuke Okita

    (Kyoto University)

  • Simon R. Tomlinson

    (University of Edinburgh)

  • Kosuke Yusa

    (Wellcome Sanger Institute
    Kyoto University)

  • Keisuke Kaji

    (University of Edinburgh)

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.

Suggested Citation

  • Daniel F. Kaemena & Masahito Yoshihara & Meryam Beniazza & James Ashmore & Suling Zhao & Mårten Bertenstam & Victor Olariu & Shintaro Katayama & Keisuke Okita & Simon R. Tomlinson & Kosuke Yusa & Keis, 2023. "B1 SINE-binding ZFP266 impedes mouse iPSC generation through suppression of chromatin opening mediated by reprogramming factors," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36097-9
    DOI: 10.1038/s41467-023-36097-9
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    References listed on IDEAS

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