KMT2E recruitment by H3 serotonylation regulates neurodevelopmental chromatin dynamics
- 1Icahn School of Medicine at Mount Sinai
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. 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). 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.
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BibTeX
@misc{ochan2026kmt2e,
title = {{KMT2E recruitment by H3 serotonylation regulates neurodevelopmental chromatin dynamics}},
author = {J. C. O'Chan and B. H. Weekley and C. Yang and M. Chen and A. M. Cunningham and S. Dutta and W. Chen and R. R. Iyer and N. I. Ahmed and B. Cetin and C. A. Sagum and B. J. Lukasak and E. Baljinnyam and Z. Christenson Wick and V. Patel and E. Andraka and A. Ramakrishnan and C. Peralta and L. Shen and H. Molina and T. Shuman and R. D. Blitzer and T. W. Muir and M. T. T. Bedford and S. G. Marro and H. Li and I. Maze},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.20.752984},
url = {https://www.biorxiv.org/content/10.64898/2026.09.20.752984v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - KMT2E recruitment by H3 serotonylation regulates neurodevelopmental chromatin dynamics
AU - J. C. O'Chan
AU - B. H. Weekley
AU - C. Yang
AU - M. Chen
AU - A. M. Cunningham
AU - S. Dutta
AU - W. Chen
AU - R. R. Iyer
AU - N. I. Ahmed
AU - B. Cetin
AU - C. A. Sagum
AU - B. J. Lukasak
AU - E. Baljinnyam
AU - Z. Christenson Wick
AU - V. Patel
AU - E. Andraka
AU - A. Ramakrishnan
AU - C. Peralta
AU - L. Shen
AU - H. Molina
AU - T. Shuman
AU - R. D. Blitzer
AU - T. W. Muir
AU - M. T. T. Bedford
AU - S. G. Marro
AU - H. Li
AU - I. Maze
PY - 2026
DA - 2026/09/20
PB - bioRxiv
DO - 10.64898/2026.09.20.752984
UR - https://www.biorxiv.org/content/10.64898/2026.09.20.752984v1
AB - 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. 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). 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.
ER -