PT  - JOURNAL ARTICLE
AU  - Rogers, Julia M
AU  - Mimoso, Claudia A
AU  - Martin, Benjamin JE
AU  - Martin, Alexandre P
AU  - Aster, Jon C
AU  - Adelman, Karen
AU  - Blacklow, Stephen C
TI  - Notch induces transcription by stimulating release of paused RNA Polymerase II
AID  - 10.1101/2024.06.13.598853
DP  - 2024 Jan 01
TA  - bioRxiv
PG  - 2024.06.13.598853
4099  - http://biorxiv.org/content/early/2024/07/12/2024.06.13.598853.short
4100  - http://biorxiv.org/content/early/2024/07/12/2024.06.13.598853.full
AB  - Notch proteins undergo ligand-induced proteolysis to release a nuclear effector that influences a wide range of cellular processes by regulating transcription. Despite years of study, however, how Notch induces the transcription of its target genes remains unclear. Here, we comprehensively examined the response to human Notch1 across a time course of activation using high-resolution genomic assays of chromatin accessibility and nascent RNA production. Our data reveal that Notch induces target gene transcription primarily by releasing paused RNA polymerase II (RNAPII). Moreover, in contrast to prevailing models suggesting that Notch acts by promoting chromatin accessibility, we found that open chromatin was established at Notch-responsive regulatory elements prior to Notch signal induction, through SWI/SNF-mediated remodeling. Together, these studies show that the nuclear response to Notch signaling is dictated by the pre-existing chromatin state and RNAPII distribution at the time of signal activation.Competing Interest StatementS.C.B. is on the board of directors of the non-profit Institute for Protein Innovation and the Revson Foundation, is on the scientific advisory board for and receives funding from Erasca, Inc. for an unrelated project, is an advisor to MPM Capital, and is a consultant for IFM, Scorpion Therapeutics, Odyssey Therapeutics, Droia Ventures, and Ayala Pharmaceuticals for unrelated projects. J.C.A. is a consultant for Ayala Pharmaceuticals, Cellestia, Inc., SpringWorks Therapeutics, and Remix Therapeutics. K.A. is a consultant to Syros Pharmaceuticals and Odyssey Therapeutics, is on the SAB of CAMP4 Therapeutics and the Advisory Board of Molecular Cell, and received research funding from Novartis not related to this work.