One of the most puzzling aspects of common chronic inflammatory skin diseases such as psoriasis is how they become chronic. What allows an ongoing condition to stay dormant for months or even years, then seemingly spring back out of nowhere?
In 2017, Elaine Fuchs and her team at Rockefeller University tackled one piece of that puzzle by investigating a curious phenomenon: Flareups often recur in the same locations. In the process, they discovered that our skin’s stem cells can retain “memories” of past experiences in a way that (in healthy responses) prepares them to heal injuries faster in the future. If these responses become dysfunctional, however, “bad” memories can make the tissue hypersensitive to environmental triggers and lead to chronic inflammation, as in psoriasis.
Whether good or bad, it remained a mystery as to how memories of past inflammation can persist for years. Now Fuchs’ team has identified tantalizing clues. In a new paper in Science , they identify key new epigenetic drivers of memory persistence. Using a combination of wet lab research and deep machine learning, they pinpoint distinct genetic sequences that propel a handful of critical memories into the years-long timeframes that underpin chronic disease.
“The findings could provide valuable inroads for developing new therapeutic strategies for chronic inflammation and possibly other human conditions such as cancer, pain, and weight regain, where the ability of our body’s cells and tissues to keep a record of past experiences may have deleterious consequences,” says Fuchs, who heads the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development .
Memory domains
In 2017, the team discovered the first evidence that tissues harbor inflammatory memory —long thought to be the domain of immune cells alone. In 2021, they identified a mechanism https://www.rockefeller.edu/news/30777-cells-remember-inflammation/ that establishes memory by first opening up parts of the genome during inflammation and then keeping these regions open and ready for the next encounter, even after inflammation quiets down.
They showed that the inflammatory transcription factor STAT3 and general stress factor FOS-JUN work together to coordinate the activation of initial response, while host cell transcription factors latch onto the exposed DNA and keep it in a ready state. In this new, open state, only FOS-JUN are needed to reactivate gene expression, which explains why many kinds of stress can set off a subsequent inflammatory flare. Many key components of this mechanism have since been recognized as generalizable mediators of inflammatory memory in a diverse array of cell types and species.
In the 2021 study, the researchers found nearly 1,000 chromatin regions (“memory domains”) that were newly opened by a psoriasis-like flareup in mice and remained open a month after the flare died down.
“In our initial understanding of how inflammatory memory worked, we couldn’t distinguish which, if any, of these regions might last long enough to have consequence for chronic human disease,” says co-first author Christopher Cowley, a former graduate student in Fuchs’ lab.
“Considering that people can experience disease flares many months or even years apart, we wanted to find out how long we could recognize signs of prior acute inflammation in mice and what determines longevity,” adds graduate student Sairaj Sajjath, another co-first author.
A model of persistence
Seeking answers, the researchers first gave a bout of psoriasis to mice when they were young. They discovered that about 10–15% of the memories that persisted a month later stuck around even to the end of the mouse’s life (~2 years). To see why these long-term memories lingered while their short-term counterparts faded within six months, they analyzed the DNA sequence characteristics within each of the memories by using a deep learning model customized by the third co-first author, Luis Soto-Ugaldi, a graduate student in the labs of both Fuchs and Memorial Sloan Kettering computational systems biologist Dana Pe’er .
“When we compared the DNA sequences of short and long-term memory domains, they looked very similar in terms of the numbers and kinds of transcription factor binding sites,” says Soto-Ugaldi. “We realized we needed to develop a new metric that specifically captures memory persistence across time, not just total accessibility at any one point.”
Soto-Ugaldi’s adaptation, called PersistNet, quickly identified a telling trait: The longest lasting memory domains had an unusually high frequency of CpG dinucleotides—short DNA sequences of cytosine followed by guanine, which are known to play a key role in gene regulation. In fact, the model predicted that CpG density hardwires a timer into every memory domain: The more CpG’s, the longer the memory.
When they tested the prediction, that’s exactly what they found. “Looking across all 1,000 memory domains, we discovered that these nucleotide densities alone, and no other DNA sequence pattern, could distinguish how long each memory would linger,” says Sajjath.
Back in the lab, the team discovered that these genetically wired densities enabled a host of epigenetic changes in memory domains, including DNA demethylation (the removal of a methyl group specifically found on CpG dinucleotides); the binding of transcription factors that prefer demethylated states; and the recruitment of a histone variant called H2A.Z, which preferentially seeks out demethylated sites and boosts chromatin accessibility while staving off future re-methylation. Together, these changes stabilized the open chromatin formation and its gene-priming activity. As the authors discovered, this structure could crucially be passed down across cellular generations, essentially keeping the doors open for life.
“This really fills out the picture of what we knew from our earlier research,” Cowley says. “At the front end, you still need that acute inflammatory experience to open up the chromatin, as those transcription factors we identified several years ago get the process going. Then, depending on how much CpG you dial in, you either have a short-term or a long-term memory.”
The results also solved a long-standing paradox in the field, Sajjath says. “There’s been speculation that epigenetically encoded memories dilute over time through cell divisions, and yet we know they somehow persist between psoriatic flares, for example. Our study closes the gap between the mechanistic understanding of memory persistence and the physiological manifestations that we see in clinical settings and in the lab.”
The researchers next plan to look closer at the differences between good memories—such as those that enable faster wound healing—and bad memories, such as those that lead to chronic inflammation like psoriasis.
“We’ve spent more time looking at beneficial memories, so now we want to look more at the maladaptive ones that are likely to increase the propensity to chronic inflammatory disease and cancer,” Fuchs says. “Identifying the unique characteristics of bad memories may help us to break the cycle of inflammatory disease.”
Science
Distinctive DNA sequence features define epigenetic longevity of inflammatory memory
26-Mar-2026