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NSD1 deposits Histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons [ChIP-seq in vivo]

ABSTRACT: During postnatal development the DNA methyltransferase DNMT3A deposits high levels of nonCG cytosine methylation in neurons. This unique methylation is critical for transcriptional regulation in the mature mammalian brain, and loss of this mark is implicated in DNMT3Aassociated neurodevelopmental disorders (NDDs). The mechanisms determining genomic nonCG methylation profiles are not well defined however, and it is unknown if this pathway is disrupted in additional NDDs. Here we show 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. Brain-specific deletion of NSD1, the H3K36 methyltransferase mutated in the NDD Sotos syndrome, disrupts megabase-scale H3K36me2 patterns, causing alterations in non-CG methylation and transcription that overlap models of DNMT3A disorders. Our findings indicate that H3K36me2 deposited by NSD1 is an important determinant of neuronal non-CG DNA methylation and implicates disruption of this methylation in Sotos syndrome.

ORGANISM(S): Mus musculus

PROVIDER: GSE212841 | GEO | 2023/07/07

REPOSITORIES: GEO

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NSD1 deposits Histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons [ChIP-seq vitro]

Project description:During postnatal development the DNA methyltransferase DNMT3A deposits high levels of nonCG cytosine methylation in neurons. This unique methylation is critical for transcriptional regulation in the mature mammalian brain, and loss of this mark is implicated in DNMT3Aassociated neurodevelopmental disorders (NDDs). The mechanisms determining genomic nonCG methylation profiles are not well defined however, and it is unknown if this pathway is disrupted in additional NDDs. Here we show 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. Brain-specific deletion of NSD1, the H3K36 methyltransferase mutated in the NDD Sotos syndrome, disrupts megabase-scale H3K36me2 patterns, causing alterations in non-CG methylation and transcription that overlap models of DNMT3A disorders. Our findings indicate that H3K36me2 deposited by NSD1 is an important determinant of neuronal non-CG DNA methylation and implicates disruption of this methylation in Sotos syndrome.

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Project description:Enzymes catalyzing CpG methylation in DNA, including DNMT1 and DNMT3A/B, are indispensable for mammalian tissue development and homeostasis. They are also implicated in human developmental disorders and cancers, supporting a critical role of DNA methylation during cell fate specification and maintenance. Recent studies suggest that histone post-translational modifications (PTMs) are involved in specifying patterns of DNMT localization and DNA methylation at promoters and actively transcribed gene bodies. However, mechanisms governing the establishment and maintenance of intergenic DNA methylation remain poorly understood. Germline mutations in DNMT3A lead to a childhood overgrowth syndrome that is phenotypically overlapping with Sotos syndrome caused by haploinsufficiency of NSD1, a histone methyltransferase catalyzing di-methylation on H3K36 (H3K36me2), pointing to a potential mechanistic link between the two disorders. Here we report that NSD1-mediated H3K36me2 is required for recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows binding and activity of DNMT3A are co-localized with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of NSD1 and its paralogue NSD2 in mouse and human cells redistributes DNMT3A to H3K36me3-marked gene bodies and reduces intergenic DNA methylation. NSD1 mutant tumors and Sotos patient samples are also associated with intergenic DNA hypomethylation. Consistently, PWWP-domain of DNMT3A shows dual recognition of H3K36me2/3 in vitro with a higher binding affinity towards H3K36me2, which is abrogated by overgrowth syndrome-derived missense mutations. Taken together, our study uncovers a trans-chromatin regulatory pathway that, when perturbed, promotes neoplastic and developmental overgrowth.

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