KMT2E recruitment by H3 serotonylation regulates neurodevelopmental chromatin dynamics

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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.
Funding Information
  • National Institute of Mental Health (R01 MH116900)
  • National Institute of Mental Health (F32 MH140478)
  • National Institute of Mental Health (F32 MH126534)
  • National Institute of Mental Health (K01 MH139990)
  • National Institute of Neurological Disorders and Stroke (R21 NS130319)
  • National Institute of Neurological Disorders and Stroke (F31 NS132558)
  • National Institute of Neurological Disorders and Stroke (F99 NS139541)
  • National Institutes of Health (F30 AG090096)
  • National Institute on Drug Abuse (T32ADA007135)
  • Howard Hughes Medical Institute
  • Cindy Silvian Foundation

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