Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout.

TitleHistone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout.
Publication TypeJournal Article
Year of Publication2021
AuthorsZhao, S, Chuh, KN, Zhang, B, Dul, BE, Thompson, RE, Farrelly, LA, Liu, X, Xu, N, Xue, Y, Roeder, RG, Maze, I, Muir, TW, Li, H
JournalProc Natl Acad Sci U S A
Volume118
Issue6
Date Published2021/02/09
ISSN1091-6490
KeywordsChromatin, Glutamine, Histones, Humans, Lysine, Methylation, Protein Binding, Protein Processing, Post-Translational, Serotonergic Neurons
Abstract

Serotonylation of glutamine 5 on histone H3 (H3Q5ser) was recently identified as a permissive posttranslational modification that coexists with adjacent lysine 4 trimethylation (H3K4me3). While the resulting dual modification, H3K4me3Q5ser, is enriched at regions of active gene expression in serotonergic neurons, the molecular outcome underlying H3K4me3-H3Q5ser crosstalk remains largely unexplored. Herein, we examine the impact of H3Q5ser on the readers, writers, and erasers of H3K4me3. All tested H3K4me3 readers retain binding to the H3K4me3Q5ser dual modification. Of note, the PHD finger of TAF3 favors H3K4me3Q5ser, and this binding preference is dependent on the Q5ser modification regardless of H3K4 methylation states. While the activity of the H3K4 methyltransferase, MLL1, is unaffected by H3Q5ser, the corresponding H3K4me3/2 erasers, KDM5B/C and LSD1, are profoundly inhibited by the presence of the mark. Collectively, this work suggests that adjacent H3Q5ser potentiates H3K4me3 function by either stabilizing H3K4me3 from dynamic turnover or enhancing its physical readout by downstream effectors, thereby potentially providing a mechanism for fine-tuning critical gene expression programs.

DOI10.1073/pnas.2016742118
Alternate JournalProc Natl Acad Sci U S A
PubMed ID33526675
PubMed Central IDPMC8017887
Grant ListF32 GM129935 / GM / NIGMS NIH HHS / United States
R01 MH116900 / MH / NIMH NIH HHS / United States
P01 CA196539 / CA / NCI NIH HHS / United States
R01 CA204639 / CA / NCI NIH HHS / United States
DP1 DA042078 / DA / NIDA NIH HHS / United States
R01 CA129325 / CA / NCI NIH HHS / United States
R21 DA044767 / DA / NIDA NIH HHS / United States
R37 GM086868 / GM / NIGMS NIH HHS / United States
MQ15FIP100011 / MQ_ / MQ: Transforming Mental Health / United Kingdom