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

Kaemena, Daniel F. ; Yoshihara, Masahito ; Beniazza, Meryam ; Ashmore, James ; Zhao, Suling ; Bertenstam, Mårten LU ; Olariu, Victor LU ; Katayama, Shintaro ; Okita, Keisuke and Tomlinson, Simon R. , et al. (2023) In Nature Communications 14(1). p.488-488
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
14
issue
1
pages
1 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85147151005
  • pmid:36717582
ISSN
2041-1723
DOI
10.1038/s41467-023-36097-9
project
Computational Science for Health and Environment
language
English
LU publication?
yes
id
fd381890-8f07-44a4-a2b5-bc8b34942a23
date added to LUP
2023-02-10 15:36:24
date last changed
2024-06-27 06:11:16
@article{fd381890-8f07-44a4-a2b5-bc8b34942a23,
  abstract     = {{<p>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.</p>}},
  author       = {{Kaemena, Daniel F. and Yoshihara, Masahito and Beniazza, Meryam and Ashmore, James and Zhao, Suling and Bertenstam, Mårten and Olariu, Victor and Katayama, Shintaro and Okita, Keisuke and Tomlinson, Simon R. and Yusa, Kosuke and Kaji, Keisuke}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{488--488}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{B1 SINE-binding ZFP266 impedes mouse iPSC generation through suppression of chromatin opening mediated by reprogramming factors}},
  url          = {{http://dx.doi.org/10.1038/s41467-023-36097-9}},
  doi          = {{10.1038/s41467-023-36097-9}},
  volume       = {{14}},
  year         = {{2023}},
}