Journal article
Mapping the epigenomic landscape of human monocytes following innate immune activation reveals context-specific mechanisms driving endotoxin tolerance
- Abstract:
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Background: Monocytes are key mediators of innate immunity to infection, undergoing profound and dynamic changes in epigenetic state and immune function which are broadly protective but may be dysregulated in disease. Here, we aimed to advance understanding of epigenetic regulation following innate immune activation, acutely and in endotoxin tolerant states.
Methods: We exposed human primary monocytes from healthy donors (n = 6) to interferon-γ or differing combinations of endotoxin (lipopolysaccharide), including acute response (2 h) and two models of endotoxin tolerance: repeated stimulations (6 + 6 h) and prolonged exposure to endotoxin (24 h). Another subset of monocytes was left untreated (naïve). We identified context-specific regulatory elements based on epigenetic signatures for chromatin accessibility (ATAC-seq) and regulatory non-coding RNAs from total RNA sequencing.
Results: We present an atlas of differential gene expression for endotoxin and interferon response, identifying widespread context specific changes. Across assayed states, only 24–29% of genes showing differential exon usage are also differential at the gene level. Overall, 19.9% (6,884 of 34,616) of repeatedly observed ATAC peaks were differential in at least one condition, the majority upregulated on stimulation and located in distal regions (64.1% vs 45.9% of non-differential peaks) within which sequences were less conserved than non-differential peaks. We identified enhancer-derived RNA signatures specific to different monocyte states that correlated with chromatin accessibility changes. The endotoxin tolerance models showed distinct chromatin accessibility and transcriptomic signatures, with integrated analysis identifying genes and pathways involved in the inflammatory response, detoxification, metabolism and wound healing. We leveraged eQTL mapping for the same monocyte activation states to link potential enhancers with specific genes, identifying 1,946 unique differential ATAC peaks with 1,340 expression associated genes. We further use this to inform understanding of reported GWAS, for example involving FCHO1 and coronary artery disease.
Conclusion: This study reports context-specific regulatory elements based on transcriptomic profiling and epigenetic signatures for enhancer-derived RNAs and chromatin accessibility in immune tolerant monocyte states, and demonstrates the informativeness of linking such elements and eQTL to inform future mechanistic studies aimed at defining therapeutic targets of immunosuppression and diseases.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 7.5MB, Terms of use)
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- Publisher copy:
- 10.1186/s12864-023-09663-0
Authors
- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 203141/Z/16/Z
- 204969/Z/16/Z
- 090532/Z/09/Z
- Publisher:
- BioMed Central
- Journal:
- BMC Genomics More from this journal
- Volume:
- 24
- Issue:
- 1
- Article number:
- 595
- Publication date:
- 2023-10-07
- Acceptance date:
- 2023-09-08
- DOI:
- EISSN:
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1471-2164
- Pmid:
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37805492
- Language:
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English
- Keywords:
- Pubs id:
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1547181
- Local pid:
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pubs:1547181
- Deposit date:
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2024-08-06
Terms of use
- Copyright holder:
- Amarasinghe et al.
- Copyright date:
- 2023
- Rights statement:
- Copyright © 2023, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
- Notes:
- For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
- Licence:
- CC Attribution (CC BY)
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