Chromatin Looping Links Target Genes with Genetic Risk Loci for Dermatological Traits
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Abstract
Abstract Chromatin looping between regulatory elements and gene promoters presents a potential mechanism whereby disease risk variants affect their target genes. Here we use H3K27ac HiChIP, a method for assaying the active chromatin interactome in two cell lines: keratinocytes and skin derived CD8+ T cells. We integrate public datasets for a lymphoblastoid cell line and primary CD4+ T cells and identify gene targets at risk loci for skin-related disorders. Interacting genes enrich for pathways of known importance in each trait, such as cytokine response (psoriatic arthritis, psoriasis) and replicative senescence (melanoma). We show examples of how our analysis can inform changes in the current understanding of multiple psoriasis associated risk loci. For example, the variant rs10794648, which is generally assigned to IFNLR1 , was linked to GRHL3 in our dataset, a gene essential in skin repair and development. Our findings, therefore, indicate a renewed importance of skin related factors in the risk of disease. Abstract Figure Graphical Abstract In this article we take disease associated variants from 5 dermatological conditions and use cell type specific datasets to map genes that could be affected by these variants, providing insight into disease mechanisms.
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Using techniques with antibodies to enhancer- and promoter-associated histone modifications or RNA polymerase has revealed large numbers of 3D enhancer-promoter contacts.
“Using these techniques with antibodies to enhancer- and promoter-associated histone modifications or those to RNA polymerase has also revealed large numbers of 3D enhancer–promoter contacts [244, 295–301].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [299]
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Javierre, B. M., Burren, O. S., Wilder, S. P., Kreuzhuber, R., Hill, S. M., Sewitz, S., Cairns, J., Wingett, S. W., Várnai, C., Thiecke, M. J., et al. (2016) · Cell · doi:10.1016/j.cell.2016.09.037 · Cited by 1,046 · see citing works
Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression
Schmiedel, B. J., Singh, D., Madrigal, A., Valdovino-Gonzalez, A. G., White, B. M., Zapardiel-Gonzalo, J., Ha, B., Altay, G., Greenbaum, J. A., McVicker, G., et al. (2018) · Cell · doi:10.1016/j.cell.2018.10.022 · Cited by 867 · see citing works
A compendium of chromatin contact maps reveals spatially active regions in the human genome
Schmitt, A. D., Hu, M., Jung, I., Xu, Z., Qiu, Y., Tan, C. L., Li, Y., Lin, S., Lin, Y., Barr, C. L., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.10.061 · Cited by 866 · see citing works
Mumbach, M. R., Satpathy, A. T., Boyle, E. A., Dai, C., Gowen, B. G., Cho, S. W., Nguyen, M. L., Rubin, A. J., Granja, J. M., Kazane, K. R., et al. (2017) · Nature Genetics · doi:10.1038/ng.3963 · Cited by 490 · cited 3× · see citing works
“Because the disorders studied have a significant immune component, we include in our analysis publicly available HiChIP data for naı̈ve CD4þ T cells and a B-cell‒like lymphoblastoid cell line (Mumbach et al., 2017) reprocessed with the latest computational tools to investigate the GWAS-associated loci, which might be…”
BackgroundMethodCHiCAGO: robust detection of DNA looping interactions in Capture Hi-C data
Cairns, J., Freire-Pritchett, P., Wingett, S. W., Várnai, C., Dimond, A., Plagnol, V., Zerbino, D., Schoenfelder, S., Javierre, B.-M., Osborne, C., et al. (2016) · Genome Biology · doi:10.1186/s13059-016-0992-2 · Cited by 417 · see citing works
Rubin, A. J., Barajas, B. C., Furlan-Magaril, M., Lopez-Pajares, V., Mumbach, M. R., Howard, I., Kim, D. S., Boxer, L. D., Cairns, J., Spivakov, M., et al. (2017) · Nature Genetics · doi:10.1038/ng.3935 · Cited by 293 · cited 3× · see citing works
“Although these techniques are very promising, there has been a lack of studies in disease-relevant cell types, and as recently evidenced, both chromatin interactions and gene regulation are cell type and stimulation specific (Burren et al., 2017; Dixon et al., 2012; Hansen et al., 2018; Mumbach et al., 2017; Rao et al…”
BackgroundRecent evidence that TADs and chromatin loops are dynamic structures
Hansen, A. S., Cattoglio, C., Darzacq, X., & Tjian, R. (2018) · Nucleus · doi:10.1080/19491034.2017.1389365 · Cited by 266 · see citing works
Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation
Siersbæk, R., Madsen, J. G. S., Javierre, B. M., Nielsen, R., Bagge, E. K., Cairns, J., Wingett, S. W., Traynor, S., Spivakov, M., Fraser, P., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.04.010 · Cited by 243 · cited 1× · see citing works
“Although these techniques are very promising, there has been a lack of studies in disease-relevant cell types, and as recently evidenced, both chromatin interactions and gene regulation are cell type and stimulation specific (Burren et al., 2017; Dixon et al., 2012; Hansen et al., 2018; Mumbach et al., 2017; Rao et al…”
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Cited by
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Transcriptional enhancers and their communication with gene promoters
Ray-Jones, H., & Spivakov, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03903-w · Cited by 81 · see citing works
Self-citation
- Authors
- Shi, C., Ray-Jones, H., Ding, J., Duffus, K., Fu, Y., Gaddi, V. P., Gough, O., Hankinson, J., Martin, P., McGovern, A., Yarwood, A., Gaffney, P., Eyre, S., Rattray, M., Warren, R. B., & Orozco, G.
- Affiliations
- University of Manchester (GB)
- Manchester Academic Health Science Centre (GB)
- Oklahoma Medical Research Foundation (US)
- Corresponding author
- Shi, Chenfu
- ORCID
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2021-08
- Volume
- 141
- Issue
- 8
- Pages
- 1975-1984
- ISSN
- 0022-202X (ISSN-L)
- PMC
- PMC8315765
- OpenAlex
- W3133478475
- Cited by
- 32
- References
- 8
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 1
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, cc-by)
- Funders
- Wellcome Trust (207491/Z/17/Z, 215207/Z/19/Z)
- Manchester Biomedical Research Centre
- Medical Research Council (MR/N00017X/1)
- University of Manchester
- Versus Arthritis (21754)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- chromatin looping, disease risk loci, psoriasis, psoriatic arthritis, melanoma, replicative senescence, cytokine response, keratinocytes, CD8+ T cells, CD4+ T cells, interferon lambda receptor 1, GRHL3, skin repair, genetic risk variants
- MeSH terms
- Chromatin, DNA-Binding Proteins, Enhancer Elements, Genetic, Humans, Promoter Regions, Genetic, Skin Diseases, Transcription Factors, Linkage Disequilibrium, Receptors, Interferon, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Chromatin Assembly and Disassembly, Cell Line, Tumor, Genome-Wide Association Study, Datasets as Topic
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