Clonal hematopoiesis-associated DNMT3A mutations derepress bivalent Polycomb target genes and enhance macrophage migration
- 1University of California Irvine
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.
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BibTeX
@misc{lee2026clonal,
title = {{Clonal hematopoiesis-associated DNMT3A mutations derepress bivalent Polycomb target genes and enhance macrophage migration}},
author = {Y. Lee and P. K. Farahat and J. P. Nguyen and Y. Takahashi and J.-Y. Lim and X. Huang and C. Brzechffa and M. E. S. Wheeler and H.-J. Yang and J. Lee and Z. S. Pope and D. J. Lu and A. N. Rudrapatna and A. P. Pankow and X. Chen and H. Yun and M. T. Weirauch and I. Marazzi and B. R. Rosenberg and E. R. Miraldi and E. P. Papapetrou and S. A. Villalta and A. G. Fleischman and M. Byun},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.754138},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.754138v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Clonal hematopoiesis-associated DNMT3A mutations derepress bivalent Polycomb target genes and enhance macrophage migration
AU - Y. Lee
AU - P. K. Farahat
AU - J. P. Nguyen
AU - Y. Takahashi
AU - J.-Y. Lim
AU - X. Huang
AU - C. Brzechffa
AU - M. E. S. Wheeler
AU - H.-J. Yang
AU - J. Lee
AU - Z. S. Pope
AU - D. J. Lu
AU - A. N. Rudrapatna
AU - A. P. Pankow
AU - X. Chen
AU - H. Yun
AU - M. T. Weirauch
AU - I. Marazzi
AU - B. R. Rosenberg
AU - E. R. Miraldi
AU - E. P. Papapetrou
AU - S. A. Villalta
AU - A. G. Fleischman
AU - M. Byun
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.754138
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.754138v1
AB - 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.
ER -