Biology subjects

Byun, M.

Publications and source records attributed to Byun, M..

4 recordsLinked to original sources

bioRxiv2026

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

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.

cell biology↗

bioRxiv2025

Convergent DNA Methylation Abnormalities at Bivalent Chromatin in Human Growth Disorders

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 chromatin--marked by both active and repressive chromatin 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 chromatin as a potential driver of abnormal growth phenotypes.

genomics↗

bioRxiv2021

Effect of chronic JUUL aerosol inhalation on inflammatory states of the brain, lung, heart and colon in mice

While health effects of conventional tobacco are well defined, data on vaping devices, including the most popular e-cigarette JUUL, are less established. Prior acute e-cigarette studies demonstrated inflammatory and cardiopulmonary physiology changes while chronic studies demonstrated extra-pulmonary effects, including neurotransmitter alterations in reward pathways. In this study we investigated effects of chronic flavored JUUL aerosol inhalation on inflammatory markers in brain, lung, heart, and colon. JUUL induced upregulation of cytokine and chemokine gene expression and increased HMGB1 and RAGE in the nucleus accumbens. Inflammatory gene expression increased in colon, and cardiopulmonary inflammatory responses to acute lung injury with lipopolysaccharide were exacerbated in the heart. Flavor-dependent changes in several responses were also observed. Our findings raise concerns regarding long-term risks of e-cigarette use as neuroinflammation may contribute to behavioral changes and mood disorders, while gut inflammation has been tied to poor systemic health and cardiac inflammation to development of heart disease. One Sentence SummaryChronic, daily inhalation of pod-based e-cigarette aerosols alters the inflammatory state across multiple organ systems in mice.

immunology↗

bioRxiv2020

Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models.

The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (Top1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of Top1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing Top1 inhibitors for COVID-19 in humans.

microbiology↗