2026-03-26 ロックフェラー大学
＜関連情報＞
- https://www.rockefeller.edu/news/39193-key-driver-of-long-term-inflammatory-memory-identified/
- https://www.science.org/doi/10.1126/science.adz6830
- https://www.nature.com/articles/nature24271
特徴的なDNA配列特性が炎症記憶のエピジェネティックな持続性を規定する Distinctive DNA sequence features define epigenetic longevity of inflammatory memory
Christopher J. Cowley, Sairaj M. Sajjath, Luis F. Soto-Ugaldi, Mara Steiger, […] , and Elaine Fuchs
Science Published:26 Mar 2026
DOI:https://doi.org/10.1126/science.adz6830
Editor’s summary
Epithelial stem cells retain a memory of prior inflammation that augments the response of the skin to subsequent insults. Cowley et al. profiled DNA accessibility in epidermal stem cells to understand how a psoriasis-like inflammation in young adult mice was retained in aged animals (see the Perspective by Blot and Sapieha). A small subset of DNA regions that increased in accessibility after inflammation remained open for more than a year and were thus poised to allow access for transcription during this time. These accessible regions were characterized by DNA sequences known as CpG sites, demethylated DNA, and the acquisition of a nucleosome-destabilizing histone variant. These epigenetic modifications to DNA and chromatincan persist as cells divide, allowing the memory of inflammation to be retained by the skin through the lifetime of a mouse —Sarah H. Ross
Structured Abstract
INTRODUCTION
Organisms adapt and learn from environmental stress. Plants that survive one pathogen broaden their resistance to others. Skin exposed to acute inflammation heals future wounds faster. Although evolutionarily advantageous, these memories can turn maladaptive, elevating chronic disease risks that, for skin, can mean psoriasis or atopic dermatitis; for lung, asthma and chronic respiratory diseases; and for intestine, inflammatory bowel disease. Increasing evidence suggests that inflammatory memories may also prime and perpetuate cancers. As our tissues confront ever-changing environments, ways to minimize maladaptive memories while bolstering beneficial ones become urgent, necessitating an understanding of the molecular mechanisms involved.
Contrasting with adaptive immunity, “trained immunity” is driven solely by epigenetics and extends beyond immune cells to other cell types and tissues. Our current understanding suggests that during inflammation, stimulus-specific transcription factors (TFs) act in concert with the general-stress TF c-FOS/c-JUN [i.e., activator protein 1 (AP1)] to open chromatin around target stress-response genes, establish enhancer-associated histone modifications, and recruit the transcriptional machinery. Cell type–specific TFs take advantage of this accessible state, and as inflammation subsides, they keep memory chromatin open and transcriptionally poised until future stress recalls c-FOS/c-JUN to jump-start the hyperactivation of associated genes.
RATIONALE
The endurance of inflammatory memory lies at the heart of its physiological relevance. In humans, vaccines that provoke trained immunity confer broad pathogen protection for years and even decades. In chronic disease, inflammatory bouts can be resolved for years before they spring back, often with greater severity. Our current understanding of inflammatory memory falls short of explaining this perdurance. Using epidermal stem cells of murine skin, we sought to uncover how functional inflammatory memories last. Epigenetic landscapes are largely reset with cell division, necessitating their reestablishment to be heritably propagated. Is long-lasting memory thus the sole purview of rarely dividing cells and/or ones that exist within a specialized niche? If not, how is epigenetic memory propagated through cellular generations? Do certain memory-associated genes receive priority for longevity, and, if so, what mechanisms endow them with a license for persistence?
RESULTS
Epidermal stem cells exposed to a psoriasis-like skin flare acquire epigenetic memories that subsequently persist after pathology and transcription return to baseline. By investigating their retention over 2 years, we learned that while most memories wane, ~10% persist with long-term functional consequences. By single-cell sequencing, we showed that these adaptations are not limited to rarely dividing cells or to regional locales.
Seeking mechanisms compatible with cell divisions, we applied deep learning to investigate chromatin dynamics from naïve to inflamed to postinflamed states. We unearthed CpG dinucleotide density as a central driver of memory perdurance. CpG-enriched memory domains became enduringly demethylated upon inflammation, binding DNA-methylation–sensitive TFs, displaying sequence-intrinsic nucleosome disaffinity, and readily gaining and sustaining the nucleosome-destabilizing, methylation-antagonizing histone variant H2A.Z. This collective epigenetic signature enabled stable propagation of inflammatory memory through time and cell division. Mining publicly available data, we suggest that this mechanism may entrench long-lasting memory across multiple cell types and inflammatory contexts.
CONCLUSION
Our findings suggest that, once activated by inflammation-induced TFs, DNA sequences orchestrate persistent poise, imparting long-lasting memory to stress-sensitive genes and profoundly affecting tissue fitness.
Model for how longevity of epigenetic memory of stress is determined.
Once memory is established by inflammatory TFs, the specialized sequences of long-term memory domains are exploited by H2A.Z and DNA demethylation. This favors an open-chromatin state and keeps domains accessible for histone modifications and both methylation-sensitive and -insensitive homeostatic TFs.
Abstract
Tissues harbor memories of inflammation, which heighten sensitivity to diverse future assaults. Whether and how these adaptations are sustained through time and cell division remain poorly understood. We show that in mice, epidermal stem cells store lifelong, functional epigenetic records of psoriasis-like skin flares. Applying deep learning to investigate these chromatin dynamics, we unearth CpG dinucleotide density as a major driver of memory persistence. Although unnecessary for inflammation-induced transcription factors to open and establish memories, CpG-enriched sequences thereafter become essential, reinforcing accessibility across cellular generations by integrating DNA demethylation, methylation-sensitive transcription factors, sequence-intrinsic nucleosome disaffinity, and the nucleosome-destabilizing histone variant H2A.Z. Thus, once activated by inflammation-induced transcription factors, DNA sequences orchestrate persistent poise, imparting long-lasting memory to stress-sensitive genes and profoundly affecting tissue fitness upon recall.
炎症記憶は皮膚上皮幹細胞を組織損傷に対して過敏にする Inflammatory memory sensitizes skin epithelial stem cells to tissue damage
Shruti Naik,Samantha B. Larsen,Nicholas C. Gomez,Kirill Alaverdyan,Ataman Sendoel,Shaopeng Yuan,Lisa Polak,Anita Kulukian,Sophia Chai & Elaine Fuchs
Nature Published:18 October 2017
DOI:https://doi.org/10.1038/nature24271
An Author Correction to this article was published on 04 July 2018
This article has been updated
Abstract
The skin barrier is the body’s first line of defence against environmental assaults, and is maintained by epithelial stem cells (EpSCs). Despite the vulnerability of EpSCs to inflammatory pressures, neither the primary response to inflammation nor its enduring consequences are well understood. Here we report a prolonged memory to acute inflammation that enables mouse EpSCs to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fuelling this memory is Aim2, which encodes an activator of the inflammasome. The absence of AIM2 or its downstream effectors, caspase-1 and interleukin-1β, erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.
