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

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: hype

SUBMITTER: Wheeler MES 

PROVIDER: S-EPMC12853687 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature