TY - JOUR
T1 - Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells
AU - Bulut-Karslioglu, Aydan
AU - Jin, Hu
AU - Kim, Yun Kyo
AU - Cho, Brandon
AU - Guzman-Ayala, Marcela
AU - Williamson, Andrew J.K.
AU - Hejna, Miroslav
AU - Stötzel, Maximilian
AU - Whetton, Anthony D.
AU - Song, Jun S.
AU - Ramalho-Santos, Miguel
N1 - Funding Information:
We thank members of the Santos Lab for input and critical reading of the manuscript, Richard Lao and members of the UCSF Institute of Human Genetics for assistance with sequencing and sonication. Samples were sequenced at UCSF Institute of Human Genetics Core Facility and Center for Advanced Technology, which is supported by the NIH (5P30CA082103). This research was supported by grants from Bloodwise and Medical Research Council plus the CRUK Manchester Centre award (C5759/A25254) to A.D.W. who is supported by the NIHR Manchester Biomedical Research Centre, 2R01CA163336 to J.S.S., the Sofja Kovalevskaja Award (Humboldt Foundation) to A.B.-K., and by NIH R01GM113014, R01GM123556, CIHR Project Grant 420231, and Canada 150 Research Chair in Developmental Epigenetics to M.R.-S.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-25088-3
DO - 10.1038/s41467-021-25088-3
M3 - Article
C2 - 34381042
AN - SCOPUS:85112273367
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4859
ER -