Genetics and environment distinctively shape the human immune cell epigenome, 2026, Wang et al

[Sly Saint]

Salk Institute researchers are debuting a new epigenetic catalog that reveals the distinct effects of genetic inheritance and life experience on various types of immune cells. The new cell type-specific database, published in Nature Genetics on January 27, 2026, helps explain individual differences in immune responses and may serve as the foundation for more effective and personalized therapeutics.

“Our immune cells carry a molecular record of both our genes and our life experiences, and those two forces shape the immune system in very different ways,” says senior author Joseph Ecker, PhD, professor, Salk International Council Chair in Genetics, and Howard Hughes Medical Institute investigator. “This work shows that infections and environmental exposures leave lasting epigenetic fingerprints that influence how immune cells behave. By resolving these effects cell by cell, we can begin to connect genetic and epigenetic risk factors to the specific immune cells where disease actually begins.”

What is the epigenome?

All the cells in your body share the same DNA sequence. And yet, there are many specialized cell types that look and act entirely differently. This diversity is due, in part, to a collection of small molecular tags called epigenetic markers, which decorate the DNA and signal which genes should be turned on or off in each cell. The many epigenetic changes in each cell collectively make up that cell’s epigenome.

Unlike the base genetic code, the epigenome is far more flexible—some epigenetic differences are strongly influenced by inherited genetic variation, while others are acquired experientially across a lifetime. Immune cells are no exception to these forces, but it was unclear whether these two types of epigenetic changes—inherited versus experiential—affected immune cells in the same way.

“The debate between nature and nurture is a long-standing discussion in both biology and society,” says co-first author Wenliang Wang, PhD, a staff scientist in Ecker’s lab. “Ultimately, both genetic inheritance and environmental factors impact us, and we wanted to figure out exactly how that manifests in our immune cells and informs our health.”

How do nature and nurture shape our immune cells? - Salk Institute for Biological Studies

Highlights Salk Institute researchers analyzed immune cells from 110 people and found that genetic differences and life experiences (sickness, vaccination history, environment) impact immune cells differently. The findings help explain why people respond differently to the same infections and...

www.salk.edu

 

[SNT Gatchaman]

Genetics and environment distinctively shape the human immune cell epigenome

Spoiler: Authors

Wang, Wenliang; Hariharan, Manoj; Ding, Wubin; Bartlett, Anna; Barragan, Cesar; Castanon, Rosa; Wang, Ruoxuan; Rothenberg, Vince; Song, Haili; Nery, Joseph R; 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

The epigenome of human immune cells is shaped by both genetics and environmental factors, yet the relative contributions of these influences remain incompletely characterized. Here we use single-nucleus methylation sequencing and assay for transposase-accessible chromatin using sequencing (ATAC–seq) to systematically explore how pathogen and chemical exposures, along with genetic variation, are associated with changes in the immune cell epigenome.

Distinct exposure-associated differentially methylated regions (eDMRs) and differentially accessible regions were identified, and a significant correlation between these two modalities was observed. Additionally, genotype-associated DMRs (gDMRs) were detected, indicating that eDMRs are enriched in regulatory regions, whereas gDMRs are preferentially located within gene body marks. Disease-associated single-nucleotide polymorphisms were frequently colocalized with methylation quantitative trait loci, providing cell-type-specific insights into the genetic basis of diseases.

These findings highlight the complex interplay between genetic and environmental factors in shaping the immune cell epigenome and advance understanding of immune cell regulation in health and disease.

Web | DOI | PDF | Nature Genetics | Open Access