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Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.

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Title: Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.
Authors: Cowley, Christopher J. (AUTHOR), Sajjath, Sairaj M. (AUTHOR), Soto-Ugaldi, Luis F. (AUTHOR), Steiger, Mara (AUTHOR), Larsen, Samantha B. (AUTHOR), Carroll, Thomas (AUTHOR), Barrows, Douglas (AUTHOR), Mattei, Alexandra (AUTHOR), Gonzales, Kevin A. U. (AUTHOR), Wang, Wei (AUTHOR), Li, Kevin (AUTHOR), Meissner, Alexander (AUTHOR), Kretzmer, Helene (AUTHOR), Pe'er, Dana (AUTHOR), Fuchs, Elaine (AUTHOR)
Source: Science. 3/26/2026, Vol. 391 Issue 6792, p1-24. 24p.
Subjects: DNA methylation, Nucleotide sequence, Stem cells, Histones, Epigenetics, Chromatin
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. 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 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 FROM AUTHOR]
Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Distinctive DNA sequence features define epigenetic longevity of inflammatory memory.
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  Data: <searchLink fieldCode="AR" term="%22Cowley%2C+Christopher+J%2E%22">Cowley, Christopher J.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Sajjath%2C+Sairaj+M%2E%22">Sajjath, Sairaj M.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Soto-Ugaldi%2C+Luis+F%2E%22">Soto-Ugaldi, Luis F.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Steiger%2C+Mara%22">Steiger, Mara</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Larsen%2C+Samantha+B%2E%22">Larsen, Samantha B.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Carroll%2C+Thomas%22">Carroll, Thomas</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Barrows%2C+Douglas%22">Barrows, Douglas</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Mattei%2C+Alexandra%22">Mattei, Alexandra</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Gonzales%2C+Kevin+A%2E+U%2E%22">Gonzales, Kevin A. U.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wang%2C+Wei%22">Wang, Wei</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Li%2C+Kevin%22">Li, Kevin</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Meissner%2C+Alexander%22">Meissner, Alexander</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kretzmer%2C+Helene%22">Kretzmer, Helene</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Pe'er%2C+Dana%22">Pe'er, Dana</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Fuchs%2C+Elaine%22">Fuchs, Elaine</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="DE" term="%22DNA+methylation%22">DNA methylation</searchLink><br /><searchLink fieldCode="DE" term="%22Nucleotide+sequence%22">Nucleotide sequence</searchLink><br /><searchLink fieldCode="DE" term="%22Stem+cells%22">Stem cells</searchLink><br /><searchLink fieldCode="DE" term="%22Histones%22">Histones</searchLink><br /><searchLink fieldCode="DE" term="%22Epigenetics%22">Epigenetics</searchLink><br /><searchLink fieldCode="DE" term="%22Chromatin%22">Chromatin</searchLink>
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  Data: 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. 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 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 FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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