KMT2C catalytic activity regulates enhancer H3K4me1 and synaptic gene expression in cortical excitatory neurons [CUT&Tag]

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental condition in which chromatin regulators represent some of the highest-confidence genetic risk factors. KMT2C encodes a COMPASS family histone methyltransferase that deposits H3K4me1 at enhancers, yet how its dysfunction contributes to ASD remains poorly understood. Here, analysis of the SPARK cohort revealed a significant enrichment of ASD-associated variants within the catalytic SET domain of KMT2C. To determine the functional consequences of impaired catalytic activity, we selectively ablated the SET domain in cortical excitatory neurons. Loss of KMT2C catalytic function resulted in robust and persistent downregulation of genes involved in synapse assembly and synaptic signaling across developmental stages and in both sexes. These transcriptional deficits were accompanied by selective reductions in H3K4me1 at associated regulatory elements. Together, our findings demonstrate that KMT2C catalytic activity is required to maintain enhancer-associated H3K4me1 and sustain synaptic gene expression in cortical excitatory neurons.