Histone H3.3 phosphorylation amplifies stimulation-induced transcription

Anja Armache, Shuang Yang, Alexia Martínez de Paz, Lexi E. Robbins, Ceyda Durmaz, Jin Q. Cheong, Arjun Ravishankar, Andrew W. Daman, Dughan J. Ahimovic, Thaís Klevorn, Yuan Yue, Tanja Arslan, Shu Lin, Tanya Panchenko, Joel Hrit, Miao Wang, Samuel Thudium, Benjamin A. Garcia, Erica Korb, Karim-Jean Armache, Scott B. Rothbart, Sandra B. Hake, C. David Allis, Haitao Li () and Steven Z. Josefowicz ()
Additional contact information
Anja Armache: Weill Cornell Medicine
Shuang Yang: Tsinghua University
Alexia Martínez de Paz: Weill Cornell Medicine
Lexi E. Robbins: Weill Cornell Medicine
Ceyda Durmaz: Weill Cornell Medicine
Jin Q. Cheong: Weill Cornell Medicine
Arjun Ravishankar: Weill Cornell Medicine
Andrew W. Daman: Weill Cornell Medicine
Dughan J. Ahimovic: Weill Cornell Medicine
Thaís Klevorn: Weill Cornell Medicine
Yuan Yue: Tsinghua University
Tanja Arslan: Ludwig-Maximilians University
Shu Lin: University of Pennsylvania
Tanya Panchenko: The Rockefeller University
Joel Hrit: Van Andel Institute
Miao Wang: New York University School of Medicine
Samuel Thudium: University of Pennsylvania Perelman School of Medicine
Benjamin A. Garcia: Ludwig-Maximilians University
Erica Korb: University of Pennsylvania Perelman School of Medicine
Karim-Jean Armache: New York University School of Medicine
Scott B. Rothbart: Van Andel Institute
Sandra B. Hake: Ludwig-Maximilians University
C. David Allis: The Rockefeller University
Haitao Li: Tsinghua University
Steven Z. Josefowicz: Weill Cornell Medicine

Nature, 2020, vol. 583, issue 7818, 852-857

Abstract: 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 genes1–3. Enriched integration of histone H3.3, the ancestral histone H3 variant, is a general feature of dynamically regulated chromatin and transcription4–7. 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 ZMYND118,9. 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.

Date: 2020
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DOI: 10.1038/s41586-020-2533-0

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