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H3K4me3 breadth is linked to cell identity and transcriptional consistency


Berenice A. Benayoun*1, Elizabeth A. Pollina*1,2, Duygu Ucar*1, Salah Mahmoudi1, Kalpana Karra1, Edith Wong1, Keerthana Devarajan1, Aaron Daugherty1, Anshul Kundaje1, Elena Mancini1, Benjamin Hitz1, Rhaki Gupta1, Thomas A. Rando3, Julie C. Baker1, Michael P. Snyder1, J. Michael Cherry1, and Anne Brunet1,2,3
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94306, USA
2Cancer Biology Program, Stanford University, Stanford CA 94305, USA
3Glenn Laboratories for the Biology of Aging at Stanford University, Stanford CA94305,USA


*These authors contributed equally to this work.
Correspondence: Anne Brunet, anne.brunet@stanford.edu

Abstract


Trimethylation of Histone H3 at Lysine 4 (H3K4me3) is a chromatin modification known to mark the transcription start sites of active genes. Here, we show that H3K4me3 domains that spread broadly over gene bodies preferentially mark genes essential for cell identity/function. Using the broadest H3K4me3 domains as a discovery tool, we identify novel regulators of neural progenitor cells. Machine learning models reveal that the broadest H3K4me3 domains represent a distinct entity, defined notably by components of the transcription elongation machinery. Genes marked by the broadest H3K4me3 domains have increased marks of elongation but also more paused polymerase at their promoters, suggesting a unique transcriptional output. Indeed, genes marked by broadest H3K4me3 domains did not exhibit increased levels, but show increased transcriptional consistency. Acute experimental perturbations of H3K4me3 breadth led to changes in transcriptional consistency. Thus, increased H3K4me3 domain breadth may ensure transcriptional precision at key cell identity/function genes.

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