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<p>Loss-of-function mutations in <i>DNMT3A</i>, a DNA methyltransferase, or <i>NSD1</i>, 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 <i>DNMT3A</i> and <i>NSD1</i>. Unexpectedly, both overgrowth- and growth restriction–associated <i>DNMT3A</i> 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 <i>DNMT3A</i> mutants and hypomethylation in overgrowth-associated <i>DNMT3A</i> or <i>NSD1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月27日

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  • Marie E. S. Wheeler,
  • Yoshiko Takahashi,
  • Jihye Lee,
  • Camille T. Perez,
  • Xiaoting Chen,
  • Yuri Lee,
  • Zachary S. Pope,
  • Daniella J. Lu,
  • Marcus Seldin,
  • Ivan Marazzi,
  • Hongseok Yun,
  • Matthew T. Weirauch,
  • Minji Byun

摘要

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.