Convergent DNA methylation abnormalities at enhancers and bivalent promoters in human growth disorders

TL;DR

This study explores how DNA methylation changes in specific genomic regions contribute to human growth disorders.

Contribution

The paper reveals shared and divergent DNA methylation patterns at enhancers and bivalent promoters in growth disorders.

Findings

Both overgrowth and growth restriction mutations in DNMT3A cause hypomethylation at shared active enhancers.

Bivalent promoters show hypermethylation in growth restriction and hypomethylation in overgrowth mutations.

Dysregulated DNA methylation at bivalent promoters is linked to abnormal growth phenotypes.

Abstract

Loss-of-function mutations in DNMT3A, a DNA methyltransferase, or NSD1, a histone methyltransferase, cause overgrowth syndromes. Conversely, disruption of the DNMT3A domain that binds NSD1-deposited H3K36 dimethylation (H3K36me2) results in growth restriction. To investigate the molecular basis of these opposing growth outcomes, we generated isogenic human embryonic stem cells carrying growth syndrome–associated mutations in DNMT3A and NSD1. Unexpectedly, both overgrowth- and growth restriction–associated DNMT3A mutations led to DNA hypomethylation in a shared subset of active enhancers, implicating H3K36me2 in directing enhancer methylation maintenance. In contrast, bivalent promoters—marked by both active and repressive histone modifications—showed divergent DNA methylation changes: hypermethylation in growth restriction-associated DNMT3A mutants and hypomethylation in overgrowth-associated DNMT3A or NSD1 loss-of-function mutants. These findings identify locus-specific DNA methylation defects as a common molecular feature and nominate dysregulated DNA methylation at bivalent promoters as a potential driver of abnormal growth phenotypes.

The online version contains supplementary material available at 10.1186/s13072-025-00650-1.

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