DNMT3A mutations linked to clonal hematopoiesis alter macrophage epigenetics and accelerate migration
The mutations derepress Polycomb target genes at specific chromatin sites and prompt earlier macrophage recruitment to injured tissues.
bioRxiv · Lee Y et al. · Paper published 25 Sep 2026
In a preprint, researchers studied human embryonic stem cell-derived macrophages to determine how DNMT3A mutations linked to clonal hematopoiesis change differentiated myeloid cell behavior. The team found that DNMT3A-mutant macrophages selectively derepressed bivalent Polycomb target genes. This activation coincided with DNA hypomethylation, decreased H3K27me3 marks, and increased promoter accessibility. Gene upregulation occurred primarily at loci with lower baseline DNA methylation and higher baseline H3K27me3, revealing that pre-existing chromatin states govern the response. This Polycomb-associated transcriptional program was also conserved in murine macrophages and enriched for pathways tied to cell migration and wound repair. Functionally, mutant macrophages displayed enhanced migration and preferential early recruitment to injured tissue.
Why it matters
Clonal hematopoiesis expands with age, and these findings explain how age-associated DNMT3A mutations directly rewire epigenetic states to alter mature immune cell trafficking.
Caveats
The findings rely on cultured human stem cell-derived and murine macrophage models and have not yet undergone peer review.
Written from the paper’s abstract, and every claim checked against it before publishing. Read the paper for the full methods and data.
The paper
Clonal hematopoiesis-associated DNMT3A mutations derepress bivalent Polycomb target genes and enhance macrophage migration
Lee Y, Farahat PK, Nguyen JP et al.
bioRxiv · 25 Sep 2026 · Preprint, not yet peer-reviewed
- Relevance
- Relevant
- News value
- Notable
- Evidence
- Cells
- Status
- Preprint
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