KMT2E recruitment by H3 serotonylation regulates neurodevelopmental chromatin dynamics
Year: 2026
Type: preprint
Abstract: ABSTRACT Histone H3 Gln 5 serotonylation (H3Q5ser) is a recently identified epigenetic modification in brain that modulates reader interactions with adjacent H3 Lys 4 trimethylation (H3K4me3) to promote transcriptional permissiveness 1,2 . However, whether H3K4me3Q5ser and its associated binding proteins regulate neurodevelopmental gene expression programs remains unknown. Here, we identified the catalytically inactive Lysine methyltransferase 2E (KMT2E) as a reader of combinatorial H3K4me3Q5ser. KMT2E preferentially binds H3K4me3Q5ser over H3K4me3 alone, and enriches at broad chromatin domains marking actively transcribed neurodevelopmental loci. Notably, heterozygous variants in KMT2E have been implicated in ODLURO syndrome, a recently characterized neurodevelopmental disorder (NDD) 3,4 . To identify the molecular mechanisms underlying ODLURO syndrome, we generated a Kmt2e transgenic mouse model that reproduces behavioral, physiological, and cellular endophenotypes associated with this and other NDDs. Furthermore, we observed that KMT2E mediates these effects by recruiting the NCoR/HDAC3 repressor complex to H3K4me3Q5ser-marked loci to restrict spreading of co-localized H3 Lys 9 acetylation (H3K9ac). Inhibition of aberrant H3K9ac spreading was sufficient to rescue transcriptional dysregulation in Kmt2e haploinsufficient neurons. These findings thus establish KMT2E as a critical reader of H3 serotonylation during neurodevelopment and provide mechanistic insights into the pathogenesis of ODLURO syndrome.
Authors: Jennifer C O’Chan, Benjamin H. Weekley, Celi Yang, Min Chen, Ashley M. Cunningham, Sohini Dutta, Winnie Chen, Rasika R. Iyer, Newaz I. Ahmed, Bulent Cetin, Cari A. Sagum, Bradley J. Lukasak, Erdene Baljinnyam, Zoé Christenson Wick, Vishwendra Patel, Emma Andraka, Aarthi Ramakrishnan, Christopher Peralta, Li Shen, Henrik Molina, Tristan Shuman, Robert D. Blitzer, Tom W. Muir, Mark T. Bedford, Samuele G. Marro, Haitao Li, Ian Maze
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: Investigating Histone 3 Dopaminylation in Parkinson's Disease, Cell-type Specific Roles for H3 Serotonylation During Critical Periods of Postnatal Brain Development and Plasticity, Interdisciplinary Training in Drug Abuse Research, Impact of histone serotonylation domain organization on neurodevelopment, Functional Role for H3 Serotonylation During Critical Periods of Postnatal Brain Development and Plasticity, Role of POU4F1 in a Novel Form of Ataxia, Mechanisms of Histone Serotonylation and MLL5 in Coordinating the Epigenome during Neurodevelopment, Molecular studies of neural histone monoaminylation in normal and aberrant brain plasticity
OpenAlex ID: W7214040406