Allele-specific transcriptional regulation of IRF4 in melanocytes is mediated by chromatin looping of the intronic rs12203592 enhancer to the IRF4 promoter
Abstract
The majority of significant single-nucleotide polymorphisms (SNPs) identified with genome-wide association studies are located in non-coding regions of the genome; it is therefore possible that they are involved in transcriptional regulation of a nearby gene rather than affecting an encoded protein's function. Previously, it was demonstrated that the SNP rs12203592, located in intron 4 of the IRF4 gene, is strongly associated with human skin pigmentation and modulates an enhancer element that controls expression of IRF4. In our study, we investigated the allele-specific effect of rs12203592 on IRF4 expression in epidermal skin samples and in melanocytic cells from donors of different skin color. We focused on the characteristics and activity of the enhancer, and on long-range chromatin interactions in melanocytic cells homozygous and heterozygous for rs12203592. We found that, irrespective of the trans-activating environment, IRF4 transcription is strongly correlated with the allelic status of rs12203592, the activity of the rs12203592 enhancer and that the chromatin features depend on the rs12203592 genotype. Furthermore, we demonstrate that the rs12203592 enhancer physically interacts with the IRF4 promoter through an allele-dependent chromatin loop, and suggest that subsequent allele-specific activation of IRF4 transcription is stabilized by another allele-specific loop from the rs12203592 enhancer to an additional regulatory element in IRF4. We conclude that the non-coding SNP rs12203592 is located in a regulatory region and affects a wide range of enhancer characteristics, resulting into modulation of the enhancer's activity, its interaction with the IRF4 promoter and subsequent allele-specific transcription of IRF4. Our findings provide another example of a non-coding SNP affecting skin color by modulating enhancer-mediated transcriptional regulation.
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Polymorphic cis-regulatory elements have been shown to affect CTCF binding and DNA looping.
“Polymorphic cis-REs have been shown to influence CTCF binding (71, 72) and DNA looping (73).”
From Variation in the Oxytocin Receptor Gene Predicts Brain Region–Specific Expression and Social Attachment (2016) · cites this paper as [72]
Variants near BNC2, particularly rs12350739, contribute to pigmentation variation through allele-specific regulatory effects.
“Variants near BNC2, particularly rs12350739, contribute to pigmentation variation through allele-specific regulatory effects ( Visser et al., 2015 ).”
From The genetic architecture of human skin pigmentation: evolution and adaptation across global populations (2026) · cites this paper as Visser et al., 2015
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- Authors
- Visser, M., Palstra, R.-J., & Kayser, M.
- Affiliations
- Erasmus MC (NL)
- Corresponding author
- Kayser, Manfred
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-01-27
- Volume
- 24
- Issue
- 9
- Pages
- 2649-2661
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2148923431
- Cited by
- 57
- References
- 46
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 5 · 2020: 4 · 2019: 1 · 2018: 4 · 2017: 6 · 2016: 8 · 2015: 7
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Erasmus+
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- IRF4, enhancers, allele-specific transcription, melanocytes, skin pigmentation, epidermis, enhancer-promoter interactions, intronic enhancer, transcriptional regulation
- MeSH terms
- Interferon Regulatory Factor-4, Alleles, Cell Line, Enhancer Elements, Genetic, Epidermis, Gene Expression Regulation, Genotype, Humans, Introns, Melanocytes, Models, Biological, Promoter Regions, Genetic, Transcription, Genetic, Trans-Activators, Polymorphism, Single Nucleotide, Chromatin Assembly and Disassembly, Chromatin Immunoprecipitation, Interferon Regulatory Factors, High-Throughput Nucleotide Sequencing
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