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

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 and Miguel Ramalho-Santos ()
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Aydan Bulut-Karslioglu: University of California, San Francisco
Hu Jin: Carl R. Woese Institute for Genomic Biology
Yun-Kyo Kim: University of Toronto
Brandon Cho: University of Toronto
Marcela Guzman-Ayala: University of California, San Francisco
Andrew J. K. Williamson: The University of Manchester
Miroslav Hejna: Carl R. Woese Institute for Genomic Biology
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
Miguel Ramalho-Santos: University of California, San Francisco

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25088-3

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