title: H3K4me3 breadth is linked to cell identity and transcriptional consistency.
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 more broadly over genes in a given cell type preferentially mark genes that are essential for the identity and function of that cell type. Using the broadest H3K4me3 domains as a discovery tool in neural progenitor cells, we identify novel regulators of these cells. Machine learning models reveal that the broadest H3K4me3 domains represent a distinct entity, characterized by increased marks of elongation. The broadest H3K4me3 domains also have more paused polymerase at their promoters, suggesting a unique transcriptional output. Indeed, genes marked by the broadest H3K4me3 domains exhibit enhanced transcriptional consistency and [corrected] increased transcriptional levels, and perturbation of H3K4me3 breadth leads to changes in transcriptional consistency. Thus, H3K4me3 breadth contains information that could ensure transcriptional precision at key cell identity/function genes.
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University, Stanford CA 94305, USA.
authors.forename: Bérénice A
authors.initials: BA
authors.lastname: Benayoun
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA; Cancer Biology Program, Stanford University, Stanford CA 94305, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Pollina
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: Duygu
authors.initials: D
authors.lastname: Ucar
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: Salah
authors.initials: S
authors.lastname: Mahmoudi
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Karra
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: Edith D
authors.initials: ED
authors.lastname: Wong
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: Keerthana
authors.initials: K
authors.lastname: Devarajan
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Daugherty
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: Anshul B
authors.initials: AB
authors.lastname: Kundaje
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Mancini
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Hitz
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: Rakhi
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Paul F. Glenn Laboratories for the Biology of Aging, Stanford University, Stanford CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, Stanford CA 94305, USA; RR&D REAP, VA Palo Alto Health Care Systems, Palo Alto, CA 94304,USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rando
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Baker
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Cherry
authors.affiliation: Department of Genetics, Stanford University, Stanford CA 94305, USA; Paul F. Glenn Laboratories for the Biology of Aging, Stanford University, Stanford CA 94305, USA; Cancer Biology Program, Stanford University, Stanford CA 94305, USA. Electronic address: anne.brunet@stanford.edu.
authors.forename: Anne
authors.initials: A
authors.lastname: Brunet
mesh_terms: D000818:Animals; D001185:Artificial Intelligence; D002477:Cells / Q000378:metabolism*; D023281:Genomics; D042421:Histone Code; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D012319:RNA Polymerase II; D008239:Lysine
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