Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, Oregon Health and Science University, Portland; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, molecular pathologist, Sonic Healthcare USA, Rye Brook, NY; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.
Role of genetics and environment in shaping the human immune cell epigenome
May 2026—DNA methylation is an epigenetic modification that plays a role in transcriptional regulation. Acquired DNA methylation arises from environmental influences to alter gene expression without changing the underlying DNA sequence. Acquired methylation can sometimes be passed on to following generations. Twin studies on transgenerational inheritance of DNA methylation have shown that the average heritability of methylation levels at cytosine–guanine dinucleotides across the genome ranges from five to 19 percent in different bulk tissues. To investigate the cell-type–specific contributions of genetic and environmental factors to the immune cell epigenome, the authors analyzed 171 peripheral blood mononuclear cell (PBMC) samples from 110 people who had defined exposures to pathogens (HIV-1, influenza A virus, methicillin-resistant Staphylococcus aureus [MRSA], methicillin-susceptible Staphylococcus aureus [MSSA], Bacillus anthracis [but with anthrax vaccine], and SARS-CoV-2) and organophosphates. Seven major immune cell types were isolated using fluorescence-activated cell sorting followed by single-cell DNA methylome profiling. PBMC samples from donors were analyzed at select time points around various pathogen or organophosphate exposures. This single-cell DNA methylome profiling was translated into signatures for mapping an exposure-driven epigenome atlas of human immune cells. Exposure-associated differentially methylated regions (eDMRs) and genotype-associated DMRs (gDMRs) were identified. EDMRs were noted to be enriched at enhancers, whereas gDMRs were predominantly found in gene bodies, highlighting divergent regulatory mechanisms. T-distributed stochastic neighbor embedding (t-SNE) analysis revealed heterogeneity in methylation profiles, resulting in more than 10 distinct clusters for each immune cell type. HIV-1, SARS-CoV-2, and MRSA/MSSA exposures were associated with distinct monocyte and CD4 and CD8 naive T-cell profiles. Infection with HIV-1 markedly changed the cell proportions among clusters, indicating that HIV-1 remodeled the global methylome and functional states of these immune cells, particularly NK cells and CD8 memory and naive T cells. The monocyte cluster, uniquely enriched with COVID samples and depleted in controls and other exposures, highlights a signature likely associated with COVID exposure. Overall, 756,575 eDMRs, including 517,698 hypomethylated and 238,877 hypermethylated eDMRs, were identified across all exposures and cell types. On average, each exposure and cell type exhibited approximately 10,000 eDMRs. SARS-CoV-2, organophosphates, and MRSA/MSSA showed the most abundant eDMRs across the majority of the cell types, highlighting their pronounced impact on the epigenetic profiles. With the evolving transition of methylation profiling in the categorization and diagnosis of neoplasms in the clinical setting, the authors’ findings provide a valuable resource for investigating the molecular mechanisms of environmental exposures. These data may one day be used to establish signatures for specific infections or exposures to further diagnostic and therapeutic decision-making for patients presenting with undiagnosed illnesses.
Wang W, Hariharan M, Ding W, et al. Genetics and environment distinctively shape the human immune cell epigenome. Nat Genet. 2026;58(2):392–403.
Correspondence: Dr. Joseph R. Ecker at ecker@salk.edu