NSD1 deposits histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons

During postnatal development, the DNA methyltransferase DNMT3A deposits high levels of non-CG cytosine methylation in neurons. This methylation is critical for transcriptional regulation, and loss of this mark is implicated in DNMT3A-associated neurodevelopmental disorders (NDDs). Here, we show in mice that genome topology and gene expression converge to shape histone H3 lysine 36 dimethylation (H3K36me2) profiles, which in turn recruit DNMT3A and pattern neuronal non-CG methylation. We show that NSD1, an H3K36 methyltransferase mutated in NDD, is required for the patterning of megabase-scale H3K36me2 and non-CG methylation in neurons. We find that brain-specific deletion of NSD1 causes altered DNA methylation that overlaps with DNMT3A disorder models to drive convergent dysregulation of key neuronal genes that may underlie shared phenotypes in NSD1- and DNMT3A-associated NDDs. Our findings indicate that H3K36me2 deposited by NSD1 is important for neuronal non-CG DNA methylation and suggest that the H3K36me2-DNMT3A-non-CG-methylation pathway is likely disrupted in NSD1-associated NDDs. [Display omitted] •Genome topology and gene expression independently pattern neuronal non-CG DNA methylation•Histone H3 lysine 36 methylation targets neuronal non-CG DNA methylation by DNMT3A•NSD1 loss causes shared epigenetic and transcriptomic changes with DNMT3A disorder models Hamagami, Wu et al. find that megabase-scale histone H3 lysine 36 dimethylation patterns target DNMT3A-mediated non-CG DNA methylation in neurons. They show that NSD1 disruption results in altered histone methylation, DNA methylation, and transcription that overlap with DNMT3A-disorder models, uncovering molecular convergence between distinct genetic causes of neurodevelopmental disease.