{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:03:52Z","timestamp":1790643832389,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,25]]},"group-title":"Cell Biology","reference-count":75,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["HL153974"],"award-info":[{"award-number":["HL153974"]}]},{"name":"National Institutes of Health","award":["AI164367"],"award-info":[{"award-number":["AI164367"]}]},{"name":"National Institutes of Health","award":["AI173314"],"award-info":[{"award-number":["AI173314"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Somatic mutations in the de novo DNA methyltransferase\n                  <jats:italic>DNMT3A<\/jats:italic>\n                  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.\n                  <jats:italic>DNMT3A<\/jats:italic>\n                  -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.\n                  <jats:italic>DNMT3A<\/jats:italic>\n                  -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.\n                <\/jats:p>","DOI":"10.64898\/2026.09.24.754138","type":"posted-content","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T12:00:33Z","timestamp":1790337633000},"source":"Crossref","is-referenced-by-count":0,"title":["Clonal hematopoiesis-associated DNMT3A mutations derepress bivalent Polycomb target genes and enhance macrophage migration"],"prefix":"10.64898","author":[{"given":"Yuri","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip K.","family":"Farahat","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of California, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer P.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Center for Epigenetics and Metabolism, University of California, Irvine, CA, USA"},{"name":"Department of Biological Chemistry, University of California, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiko","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung-Yeon","family":"Lim","sequence":"additional","affiliation":[{"name":"Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Biomedical Laboratory Science, Inje University, Gimhae, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Brzechffa","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, University of California, Irvine, Irvine, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie E. 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