Roles of histone lysine methylation in neurodevelopment and related disorders

Abstract

Neurodevelopment is a highly ordered, precisely regulated process that establishes the neurobiological foundations of cognition, thought, emotion, and behavior. Neurodevelopmental disorders (NDDs) display marked phenotypic and genetic heterogeneity and variably impair learning, daily functioning, and social adaptation. As a key epigenetic mechanism, histone lysine methylation shapes chromatin accessibility and transcriptional programs, exerting central roles in neural stem cell fate decisions, neuronal migration and circuit assembly, as well as synaptic plasticity and learning and memory. Focusing on the activating histone H3 lysine 4 (H3K4) methylation marks (H3K4me1/2/3), this review synthesizes evidence for the bidirectional regulation mediated by “writers” (the KMT2/SET/DOT1) and “erasers” (the KDM/LSD and KDM5) in NDDs, including Kabuki syndrome, Wiedemann-Steiner syndrome, autism spectrum disorder, and schizophrenia. We further outline how animal models, patient-derived brain organoids, and multi-omics atlases enhance mechanistic insight, and we discuss the translational potential of small-molecule interventions, and metabolic modulation. Together, we summarize how the precise balance of methylation writing and erasure—and its crosstalk with DNA methylation and histone acetylation—forms an epigenetic network that drives neurodevelopmental programs. Targeting this network offers testable therapeutic avenues for NDDs.

Keywords

Epigenetics / H3K4me3 / histone modification / lysine methylation / neurodevelopmental disorders

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