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Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells

Author

Listed:
  • Aydan Bulut-Karslioglu

    (University of California, San Francisco
    Max Planck Institute for Molecular Genetics)

  • Hu Jin

    (Carl R. Woese Institute for Genomic Biology
    University of Illinois, Urbana-Champaign
    Harvard Medical School)

  • Yun-Kyo Kim

    (University of Toronto)

  • Brandon Cho

    (University of Toronto)

  • Marcela Guzman-Ayala

    (University of California, San Francisco
    Senti Biosciences)

  • Andrew J. K. Williamson

    (The University of Manchester
    Thermo Fisher Scientific)

  • Miroslav Hejna

    (Carl R. Woese Institute for Genomic Biology
    University of Illinois, Urbana-Champaign)

  • Maximilian Stötzel

    (Max Planck Institute for Molecular Genetics)

  • Anthony D. Whetton

    (The University of Manchester)

  • Jun S. Song

    (Carl R. Woese Institute for Genomic Biology
    University of Illinois, Urbana-Champaign)

  • Miguel Ramalho-Santos

    (University of California, San Francisco
    University of Toronto)

Abstract

Stem and progenitor cells undergo a global elevation of nascent transcription, or hypertranscription, during key developmental transitions involving rapid cell proliferation. The chromatin remodeler Chd1 mediates hypertranscription in pluripotent cells but its mechanism of action remains poorly understood. Here we report a novel role for Chd1 in protecting genome integrity at promoter regions by preventing DNA double-stranded break (DSB) accumulation in ES cells. Chd1 interacts with several DNA repair factors including Atm, Parp1, Kap1 and Topoisomerase 2β and its absence leads to an accumulation of DSBs at Chd1-bound Pol II-transcribed genes and rDNA. Genes prone to DNA breaks in Chd1 KO ES cells are longer genes with GC-rich promoters, a more labile nucleosomal structure and roles in chromatin regulation, transcription and signaling. These results reveal a vulnerability of hypertranscribing stem cells to accumulation of endogenous DNA breaks, with important implications for developmental and cancer biology.

Suggested Citation

  • Aydan Bulut-Karslioglu & Hu Jin & Yun-Kyo Kim & Brandon Cho & Marcela Guzman-Ayala & Andrew J. K. Williamson & Miroslav Hejna & Maximilian Stötzel & Anthony D. Whetton & Jun S. Song & Miguel Ramalho-S, 2021. "Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25088-3
    DOI: 10.1038/s41467-021-25088-3
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    Cited by:

    1. Mei Sheng Lau & Zhenhua Hu & Xiaodan Zhao & Yaw Sing Tan & Jinyue Liu & Hua Huang & Clarisse Jingyi Yeo & Hwei Fen Leong & Oleg V. Grinchuk & Justin Kaixuan Chan & Jie Yan & Wee-Wei Tee, 2023. "Transcriptional repression by a secondary DNA binding surface of DNA topoisomerase I safeguards against hypertranscription," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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