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Joseph “Joe” Ecker, PhD, is an epigenetics hipster. The Salk Professor and Howard Hughes Medical Institute (HHMI) investigator has been thinking about epigenetics long before it became fashionable. Prior to epigenetics becoming tangled with claims about trauma, inheritance, and memory, Ecker was already cataloging which epigenetic signals persist, which fade, and which are artifacts. His lab has spent years mapping DNA methylation across plants, brains, and single cells. To Ecker, epigenetics has always been less about a vehicle for airy “nature vs. nurture” arguments and more about the data.
Most recently, Ecker took his epigenetic lens to a fundamental precision medicine question: when real people encounter real immune challenges, such as viral infection, vaccination, chronic disease, does that experience remain encoded in their cells? And, if so, then how? What makes this information fundamentally different from the marks written by DNA sequence alone?
In a new Nature Genetics paper, Ecker and colleagues profiled DNA methylation at single-cell resolution across immune cells from individuals exposed to real-world infections and vaccines, and the results are foundational—genetic risk and environmental exposures are encoded in the immune system in distinct ways. Ecker and colleagues’ examination at molecular resolution suggests that inherited variation shapes stable methylation patterns across gene bodies, whereas immune exposures act quickly via regulatory elements such as enhancers. Together, these layers form a structured, interpretable epigenetic record that complements genetic information.
From brain to blood
Ecker’s path into immunology came not from clinical work, but from years spent studying how cell identity and history are recorded in the brain. “We were brought into this project because of our interest in looking at changes in cell-type-specific epigenetic processes, mainly DNA methylation,” Ecker told Inside Precision Medicine. “Our lab is mostly focused on the human brain… but we got brought into this because of our expertise in looking at single-cell profiling.”
This knowledge became essential to a DARPA-funded partnership called ECHO (Epigenetic CHaracterization and Observation). This name, Ecker explained, captured the project’s central biological question: traces (echoes) of what had previously occurred in your cells. Ecker’s lab had already clearly observed this “echo” in the brain with “vestigial” enhancers—areas that are less methylated and lack active histone modifications in adult tissues but still show activity during embryonic development.
Ecker wasn’t the only one who had caught the scent of this trail, pointing to work led by the lab of Bing Ren, PhD, just across the street from Ecker at UCSD, that used groundbreaking epigenome maps of the human body’s major organs (i.e., Salk-generated body map data). In this work, Ren, who is now director of the New York Genome Center, discovered that the methylation patterns of microglia populations shift dramatically during aging. At first glance, these cells appear activated and inflammatory. But deeper analysis reveals something else—their developmental identity.
“During aging, you have a population change of your microglia in your brain,” explained Ecker. “There’s a big switch from this one population to another. We thought those must be activated microglia. But when you cluster and analyze them, you find that they’re most similar to monocytes, which can differentiate into microglia in your brain.” This identity is not coded in the transcriptional profile but rather through methylation that preserves developmental history. Ecker explained, “RNA is about something that’s happening right now. Those differential methylation changes that happened during the development of that cell, they don’t get erased. You have this information about what that cell was.”
That insight raised a natural question: If methylation preserves lineage and developmental history in immune cells, could it also record immune cell experience to infection?
Answering that question required access to human populations undergoing real immune challenges, something that Ecker doesn’t have at the Salk Institute. This is precisely where the partnership with DARPA became essential, with Tim Broderick, MD, PhD, when he was program manager, who had access to diverse cohorts.
Separating genetics from environmental response
In total, the study analyzed peripheral blood mononuclear cells (PBMCs) from 110 individuals across six different immune exposures. “We were able to collaborate with groups that were collecting PBMCs in response to various insults,” Ecker said. “We got some COVID samples before and after COVID-flu vaccinations. The military had given anthrax vaccinations during the anthrax scare.”
One particular group of samples, that of men at high risk for contracting HIV, provided a particularly rare opportunity. In that sample group were also individuals who had contracted HIV. “We had pre-infected and treated patients,” he said, “so we could compare the pre-infection, acute infection, and chronic disease populations.”
To examine these populations, Ecker’s team turned to assays with single-cell resolution because bulk measurements overlook critical structure. “There have been several studies examining blood and PBMCs,” he said. “But here we are actually sorting the cells. Even within the sorted population, there are different clusters of cells. The monocytes are not all the same.”
Analysis of data from single-nucleus methylation sequencing and assay for transposase-accessible chromatin using sequencing (ATAC–seq) found that immune challenges left distinct and interpretable methylation signatures at single-cell resolution. Different exposures produced different epigenetic architectures, or what they call differentially methylated regions (DMRs). Ecker explained, “When you contract HIV, your cells undergo a transformation. There were very specific changes that were HIV-specific but not COVID-specific. COVID populations tended to increase modified populations,” he said. “The flu was sort of transient. And HIV could have very chronic changes.”
One of the paper’s most important contributions is its demonstration that genetic and environmental influences act through different genomic compartments. “You can segregate these DMRs,” Ecker said. Some methylation patterns tracked strongly with inherited genetic variants. “Gene body-related changes are mostly associated with genetic variants,” he said. Others reflected immune exposure. “The rapid changes observed in response to the environment are primarily changes in regulatory accessibility,” Ecker said, particularly in enhancers and open chromatin regions identified by ATAC-seq. The distinction aligns with known biology. “Depending on how powerful the infection is, you can see that there are mostly changes in enhancer sequences,” he said.
Epigenetics has long struggled with skepticism over effect size, particularly when changes involve single CpGs. “It’s always been like, you have to have this giant DMR,” Ecker said. “But this study mostly found single CpGs.” What convinced the authors these signals were real was coherence. “Those single CpGs… were selective for one particular perturbation,” he said. “If it was just noise, you wouldn’t expect that.” To validate this separation, the team directly called SNPs from bisulfite sequencing data. The result was a coherent framework: inherited variation shapes stable epigenetic architecture across gene bodies, while immune experience drives dynamic regulatory changes.
Bringing epigenomics into precision medicine
The same logic is now being applied beyond immunology. “We’re using this for Alzheimer’s,” Ecker said. “If I took a skin biopsy of you and you had Alzheimer’s versus me and I did not, I could tell from the methylation pattern.”
Cancer vividly illustrates how genetic mutations can reprogram epigenetic states. A recent Science study from KAIST showed that IDH-mutant gliomas—the most common malignant brain tumors in young adults—likely arise from glial progenitor cells that acquire IDH mutations early and are spatially distributed in noncancerous brain regions far from the primary tumor. By combining deep sequencing, spatial transcriptomics, and experimental models, tumor evolution was traced back to these widely dispersed mutant progenitor cells, implicating them as the cellular origin of IDH-mutant glioma. “It’s the IDH-mutation that alters the epigenome,” explained Ecker. “That was the very first event, and that drives the rest of the cancer.”
Scaling such approaches necessitates clinical collaborations, which, like the human immune epigenome project, is a significant rate limiting factor for the Salk group. Ecker said that, so far, they’ve been able to attract attention from groups that actually have access to large population data sets. “We really need clinical partners, and that’s why I was happy to see at least we attracted some attention from groups that actually have access to large populations,” said Ecker. “Through them, we can do more large-scale studies where you have a trajectory of a large number of people with different populations, and so we would have to work with them to do something like that because we’re a not-for-profit, not a hospital.”
Ecker does not frame epigenetics as a replacement for genetics but as a missing layer. “Personalized medicine is largely focused on genetics for good reason,” he said. “But clearly there are features in the epigenome that you can’t see in the genome sequence unless you look at it.” What matters, he said, is understanding how genetic variation manifests through epigenetic regulation. “I think understanding what the individual genetic variation means in terms of the epigenome is going to be important,” Ecker said.
The Nature Genetics study was not designed to measure how long those signatures persist. “It wasn’t a study where we could follow this population for a long time,” Ecker said. “But the idea here is more about what we can see. Are there fundamental differences?” The possibility that immune history might be readable years later is already prompting interest. “I was just contacted this morning based on this paper from a company that does diagnostics,” Ecker said. “They said, ‘Hey, can we convert this to a—this is a whole gene.’”
In this view, epigenetics is neither hype nor mystery. It is a structured, cell-type-specific, and increasingly readable record of how genomes interact with real lives.
