Histone H3.3 phosphorylation amplifies stimulation-induced transcription.

TitleHistone H3.3 phosphorylation amplifies stimulation-induced transcription.
Publication TypeJournal Article
Year of Publication2020
AuthorsArmache A, Yang S, de Paz AMartínez, Robbins LE, Durmaz C, Cheong JQ, Ravishankar A, Daman AW, Ahimovic DJ, Klevorn T, Yue Y, Arslan T, Lin S, Panchenko T, Hrit J, Wang M, Thudium S, Garcia BA, Korb E, Armache K-J, Rothbart SB, Hake SB, C Allis D, Li H, Josefowicz SZ
JournalNature
Volume583
Issue7818
Pagination852-857
Date Published2020 07
ISSN1476-4687
KeywordsAnimals, Cell Cycle Proteins, Cells, Cultured, Co-Repressor Proteins, DNA-Binding Proteins, Histone-Lysine N-Methyltransferase, Histones, Humans, I-kappa B Kinase, Macrophages, Male, Methylation, Mice, Models, Molecular, Phosphorylation, Transcription, Genetic, Up-Regulation
Abstract

Complex organisms can rapidly induce select genes in response to diverse environmental cues. This regulation occurs in the context of large genomes condensed by histone proteins into chromatin. The sensing of pathogens by macrophages engages conserved signalling pathways and transcription factors to coordinate the induction of inflammatory genes. Enriched integration of histone H3.3, the ancestral histone H3 variant, is a general feature of dynamically regulated chromatin and transcription. However, how chromatin is regulated at induced genes, and what features of H3.3 might enable rapid and high-level transcription, are unknown. The amino terminus of H3.3 contains a unique serine residue (Ser31) that is absent in 'canonical' H3.1 and H3.2. Here we show that this residue, H3.3S31, is phosphorylated (H3.3S31ph) in a stimulation-dependent manner along rapidly induced genes in mouse macrophages. This selective mark of stimulation-responsive genes directly engages the histone methyltransferase SETD2, a component of the active transcription machinery, and 'ejects' the elongation corepressor ZMYND11. We propose that features of H3.3 at stimulation-induced genes, including H3.3S31ph, provide preferential access to the transcription apparatus. Our results indicate dedicated mechanisms that enable rapid transcription involving the histone variant H3.3, its phosphorylation, and both the recruitment and the ejection of chromatin regulators.

DOI10.1038/s41586-020-2533-0
Alternate JournalNature
PubMed ID32699416
PubMed Central IDPMC7517595
Grant ListR01 GM040922 / GM / NIGMS NIH HHS / United States
P01 CA196539 / CA / NCI NIH HHS / United States
K99 GM113019 / GM / NIGMS NIH HHS / United States
T32 AI134632 / AI / NIAID NIH HHS / United States
R00 GM113019 / GM / NIGMS NIH HHS / United States
R35 GM124736 / GM / NIGMS NIH HHS / United States
R01 GM115882 / GM / NIGMS NIH HHS / United States
R01 AI148416 / AI / NIAID NIH HHS / United States
R01 AI118891 / AI / NIAID NIH HHS / United States
Related Faculty: 
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