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Cited by 94Genomics and Chromatin DynamicsGenetic Associations and EpidemiologyEpigenetics and DNA Methylation

Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks

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Pelikan, Richard C., Kelly, Jennifer A., Fu, Yao, Lareau, Caleb A., Tessneer, Kandice L., Wiley, Graham B., Wiley, Mandi M., Glenn, Stuart B. +6 more·2018·Nature Communications
DOI 10.1038/s41467-018-05328-9PMC PMC6060153
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Abstract

Genetic variants can confer risk to complex genetic diseases by modulating gene expression through changes to the epigenome. To assess the degree to which genetic variants influence epigenome activity, we integrate epigenetic and genotypic data from lupus patient lymphoblastoid cell lines to identify variants that induce allelic imbalance in the magnitude of histone post-translational modifications, referred to herein as histone quantitative trait loci (hQTLs). We demonstrate that enhancer hQTLs are enriched on autoimmune disease risk haplotypes and disproportionately influence gene expression variability compared with non-hQTL variants in strong linkage disequilibrium. We show that the epigenome regulates HLA class II genes differently in individuals who carry HLA-DR3 or HLA-DR15 haplotypes, resulting in differential 3D chromatin conformation and gene expression. Finally, we identify significant expression QTL (eQTL) x hQTL interactions that reveal substructure within eQTL gene expression, suggesting potential implications for functional genomic studies that leverage eQTL data for subject selection and stratification.

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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 [296]

    The Methods (HiChIP sequencing and analysis; page unavailable) describe using an antibody to the enhancer-associated H3K27ac mark to identify long-range DNA loops. The Results (HLA-DR3 and -DR15 hQTLs differentially regulate HLA genes; page unavailable) report looping between an enhancer and the HLA-DRB1 promoter. Our copy does not show that promoter-associated histone or RNA-polymerase antibodies revealed contacts, or establish the claimed large number of enhancer–promoter contacts. (LLM, conf=0.85)

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Authors
Pelikan, R. C., Kelly, J. A., Fu, Y., Lareau, C. A., Tessneer, K. L., Wiley, G. B., Wiley, M. M., Glenn, S. B., Harley, J. B., Guthridge, J. M., James, J. A., Aryee, M. J., Montgomery, C., & Gaffney, P. M.
Affiliations
  • Oklahoma Medical Research Foundation (US)
  • Harvard University (US)
  • Cincinnati Children's Hospital Medical Center (US)
Corresponding author
Gaffney, Patrick M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-07-25
Volume
9
Issue
1
Pages
2905-2905
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-05328-9
PMC
PMC6060153
OpenAlex
W2884587337
Cited by
94
References
12
Citations by year
2026: 8 · 2025: 11 · 2024: 8 · 2023: 5 · 2022: 11 · 2021: 16 · 2020: 25 · 2019: 9 · 2018: 1
FWCI
4.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Division of Intramural Research, National Institute of Allergy and Infectious Diseases (U19AI082714)
  • U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR053483, R01AR056360, R01AR063124)
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (U54GM104938, P30GM110766)
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
histone modifications, systemic lupus erythematosus, HLA-DR3, HLA-DR15, 3D chromatin conformation, allelic imbalance, linkage disequilibrium, epigenome, lymphoblastoid cell lines, gene expression variation
MeSH terms
Chromatin, Female, Genotype, Haplotypes, Humans, Male, Linkage Disequilibrium, Genetic Predisposition to Disease, Quantitative Trait Loci, Genome-Wide Association Study

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