Clonal hematopoiesis-associated DNMT3A mutations derepress bivalent Polycomb target genes and enhance macrophage migration

Year: 2026

Type: preprint

Abstract: Somatic mutations in the de novo DNA methyltransferase DNMT3A are frequent in clonal hematopoiesis, but how they alter the function of differentiated myeloid cells remains unclear. Here, we used isogenic human embryonic stem cell-derived macrophage models to define the consequences of DNMT3A dysfunction during myeloid differentiation. DNMT3A -mutant macrophages selectively upregulated bivalent Polycomb target genes, accompanied by DNA hypomethylation, reduced H3K27me3 and increased promoter accessibility. Despite broad epigenetic changes across bivalent promoters, transcriptional derepression occurred at a subset of loci characterized by lower baseline DNA methylation and higher H3K27me3, identifying pre-existing chromatin state as a determinant of transcriptional response. This Polycomb-associated program was conserved in murine macrophages and enriched for genes involved in cell migration and wound repair. DNMT3A -mutant macrophages exhibited enhanced migration and preferential early recruitment to injured tissue. These findings link clonal hematopoiesis-associated epigenetic alterations to selective transcriptional reprogramming and altered function of differentiated myeloid cells.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.09.24.754138

Institutions: University of California, Irvine, Inje University, Icahn School of Medicine at Mount Sinai, Cincinnati Children's Hospital Medical Center, Seoul National University Hospital, University of Cincinnati

Language: English

Topic: Epigenetics and DNA Methylation

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases

Awards: Mechanistic modeling of epigenetic modifier mutations in human pluripotent stem cell-derived immune cells, Cincinnati Rheumatic Diseases Resource Center, Altered inflammatory response associated with acquired DNMT3A mutations, Gene regulatory network modeling of disease-associated DNA methylation perturbations

OpenAlex ID: W7214365769