Wang Wenliang, Hariharan Manoj, Ding Wubin, Bartlett Anna, Barragan Cesar, Castanon Rosa, Rothenberg Vince, Song Haili, Nery Joseph, Aldridge Andrew, Altshul Jordan, Kenworthy Mia, Liu Hanqing, Tian Wei, Zhou Jingtian, Zeng Qiurui, Chen Huaming, Wei Bei, Gündüz Irem B, Norell Todd, Broderick Timothy J, McClain Micah T, Satterwhite Lisa L, Burke Thomas W, Petzold Elizabeth A, Shen Xiling, Woods Christopher W, Fowler Vance G, Ruffin Felicia, Panuwet Parinya, Barr Dana B, Beare Jennifer L, Smith Anthony K, Spurbeck Rachel R, Vangeti Sindhu, Ramos Irene, Nudelman German, Sealfon Stuart C, Castellino Flora, Walley Anna Maria, Evans Thomas, Müller Fabian, Greenleaf William J, Ecker Joseph R
Genomic Analysis Laboratory, The Salk Institute for Biological Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037, USA.
Duke University School of Medicine, Bryan Research Building, 311 Research Drive, Durham, NC 27710, USA.
bioRxiv. 2025 Jan 4:2023.06.29.546792. doi: 10.1101/2023.06.29.546792.
The epigenomic landscape of human immune cells is dynamically shaped by both genetic factors and environmental exposures. However, the relative contributions of these elements are still not fully understood. In this study, we employed single-nucleus methylation sequencing and ATAC-seq to systematically explore how pathogen and chemical exposures, along with genetic variation, influence the immune cell epigenome. We identified distinct exposure-associated differentially methylated regions (eDMRs) corresponding to each exposure, revealing how environmental factors remodel the methylome, alter immune cell states, and affect transcription factor binding. Furthermore, we observed a significant correlation between changes in DNA methylation and chromatin accessibility, underscoring the coordinated response of the epigenome. We also uncovered genotype-associated DMRs (gDMRs), demonstrating that while eDMRs are enriched in regulatory regions, gDMRs are preferentially located in gene body marks, suggesting that exposures and genetic factors exert differential regulatory control. Notably, disease-associated SNPs were frequently colocalized with meQTLs, providing new cell-type-specific insights into the genetic basis of disease. Our findings underscore the intricate interplay between genetic and environmental factors in sculpting the immune cell epigenome, offering a deeper understanding of how immune cell function is regulated in health and disease.
人类免疫细胞的表观基因组格局由遗传因素和环境暴露动态塑造。然而，这些因素的相对贡献仍未完全了解。在本研究中，我们采用单核甲基化测序和ATAC-seq技术，系统地探究病原体和化学物质暴露以及遗传变异如何影响免疫细胞表观基因组。我们鉴定出了与每种暴露相对应的不同的暴露相关差异甲基化区域（eDMR），揭示了环境因素如何重塑甲基化组、改变免疫细胞状态并影响转录因子结合。此外，我们观察到DNA甲基化变化与染色质可及性之间存在显著相关性，强调了表观基因组的协同反应。我们还发现了基因型相关的DMR（gDMR），表明虽然eDMR在调控区域富集，但gDMR优先位于基因体标记中，这表明暴露和遗传因素发挥着不同的调控作用。值得注意的是，疾病相关的单核苷酸多态性（SNP）经常与甲基化数量性状位点（meQTL）共定位，为疾病的遗传基础提供了新的细胞类型特异性见解。我们的研究结果强调了遗传和环境因素在塑造免疫细胞表观基因组中的复杂相互作用，为深入了解健康和疾病状态下免疫细胞功能的调控提供了依据。
