Epigenetic dysregulation in neurodevelopmental disorders: mechanisms, vulnerabilities, and therapeutic opportunities

Abstract

Neurodevelopment requires the precise coordination of gene expression programs across developmental time, cell types, and anatomical regions. Epigenetic regulation, encompassing DNA methylation, histone modification, and three-dimensional genome organization, provides a critical interface through which genetic information, developmental cues, and environmental signals are integrated to shape neural lineage specification, circuit formation, and functional maturation of the brain. Disruption of these regulatory layers is increasingly recognized as a unifying mechanism underlying a broad spectrum of neurodevelopmental disorders (NDDs), including Fragile X syndrome (FXS), Rett syndrome (RTT), immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome, Kabuki syndrome (KS), CHARGE syndrome, and autism spectrum disorder (ASD). Recent advances in single-cell, spatial, and long-read epigenomic technologies have revealed striking cell-type–specific and regionally resolved epigenetic landscapes in the developing and mature brain, uncovering how DNA methylation dynamics, histone modifications, and higher-order chromatin architecture cooperate to regulate neuronal identity and activity-dependent gene expression. Here, we review the current understanding of these interconnected epigenetic mechanisms in normal neurodevelopment and examine how their perturbation contributes to disease pathogenesis. We further discuss emerging epigenetic-based therapeutic strategies, with an emphasis on locus-specific and programmable epigenome editing approaches that hold promise for restoring endogenous gene regulation and neuronal function.

Keywords

neurodevelopment / epigenetics / DNA methylation / histone modification / chromatin architecture / genetic disorders

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Higher Education Press 2026

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