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- Title
Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells.
- Authors
Bulut-Karslioglu, Aydan; Jin, Hu; Kim, Yun-Kyo; Cho, Brandon; Guzman-Ayala, Marcela; Williamson, Andrew J. K.; Hejna, Miroslav; Stötzel, Maximilian; Whetton, Anthony D.; Song, Jun S.; Ramalho-Santos, Miguel
- 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. The chromatin remodeler Chd1 mediates hypertranscription in embryonic stem (ES) cells and has been shown to associate with genes transcribed by RNA Polymerase (Pol) I and II. Here the authors provide mechanistic insights into this process and reveal that Chd1 is involved in protecting genome integrity at promoter regions by preventing DNA break accumulation.
- Subjects
EMBRYONIC stem cells; DOUBLE-strand DNA breaks; GENOMES; PROMOTERS (Genetics); RNA polymerases
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-25088-3