Chd1 is an ATP-dependent chromatin remodeler that binds specifically to H3K4me3 and is found at sites of active transcription 8, 9. Some of the players implicated in promoting hypertranscription are the transcription factors Myc and Yap/Taz, the RNA Polymerase regulator pTEFb and the chromatin remodeler Chd1 (reviewed in Percharde et al. It is expected that hypertranscription involves a coordinated interplay between activating transcription factors, chromatin remodelers, and RNA Polymerases. The molecular regulation of hypertranscription, or even how it differs from general transcriptional regulation, remains poorly understood. Hypertranscription has been documented to occur and play critical roles in embryonic stem (ES) cells 2, the post-implantation epiblast 3, emergence of definitive hematopoietic stem cells 4, primordial germ cells 5, and neurogenesis 6, and may take place in other settings during development, regeneration, and disease 1, 7. Hypertranscription is masked by most transcriptional profiling approaches, but has attracted renewed interest recently. One way that stem/progenitor cells cope with this demand is to enter a state of hypertranscription, which involves a global elevation of nascent transcriptional output 1. Proliferating stem and progenitor cells are net generators of new cellular biomass and therefore have high biosynthetic demand. These results reveal a vulnerability of hypertranscribing stem cells to accumulation of endogenous DNA breaks, with important implications for developmental and cancer biology. 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. 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. 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. The chromatin remodeler Chd1 mediates hypertranscription in pluripotent cells but its mechanism of action remains poorly understood. Stem and progenitor cells undergo a global elevation of nascent transcription, or hypertranscription, during key developmental transitions involving rapid cell proliferation.
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