The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index.
A Polymorphism in IRF4 Affects Human Pigmentation through a Tyrosinase-Dependent MITF/TFAP2A Pathway
Open accessAbstract
Sequence polymorphisms linked to human diseases and phenotypes in genome-wide association studies often affect noncoding regions. A SNP within an intron of the gene encoding Interferon Regulatory Factor 4 (IRF4), a transcription factor with no known role in melanocyte biology, is strongly associated with sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color. Here, we demonstrate that this SNP lies within an enhancer of IRF4 transcription in melanocytes. The allele associated with this pigmentation phenotype impairs binding of the TFAP2A transcription factor that, together with the melanocyte master regulator MITF, regulates activity of the enhancer. Assays in zebrafish and mice reveal that IRF4 cooperates with MITF to activate expression of Tyrosinase (TYR), an essential enzyme in melanin synthesis. Our findings provide a clear example of a noncoding polymorphism that affects a phenotype by modulating a developmental gene regulatory network.
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“MITF, the transcription factor known as the “master regulator of melanogenesis” due to its ability to activate many melanocyte-specific genes (Praetorius et al., 2013), recruits critical components of the SWI/SNF chromatin remodeling complex (including SMARCA2), to the promoter region of its targets (Vachtenheim et al., 2010).”
From An Unexpectedly Complex Architecture for Skin Pigmentation in Africans (2017) · cites this paper as Praetorius et al., 2013
In the citing paper
“The intronic IRF4 variant rs12203592 influences skin pigmentation, tanning response, and hair pigmentation, but shows weaker evolutionary signals than the major sweep loci ( Praetorius et al., 2013 ).”
From The genetic architecture of human skin pigmentation: evolution and adaptation across global populations (2026) · cites this paper as Praetorius et al., 2013
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Citations
Cites
1 retracted
RETRACTED: A BLOC-1 Mutation Screen Reveals that PLDN Is Mutated in Hermansky-Pudlak Syndrome Type 9
Cullinane, A. R., Curry, J. A., Carmona‐Rivera, C., Summers, C. G., Ciccone, C., Cardillo, N., Dorward, H. M., Hess, R. A., White, J. G., Adams, D. R., et al. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.05.009 · Cited by 106
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Fast and SNP-tolerant detection of complex variants and splicing in short reads
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Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination
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Melanocytes and theMicrophthalmiaTranscription Factor Network
Steingrı́msson, E., Copeland, N. G., & Jenkins, N. A. (2004) · Annual Review of Genetics · doi:10.1146/annurev.genet.38.072902.092717 · Cited by 762
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Items 201–228 of 228
Moazed, K. T. (2020) · Springer eBooks · doi:10.1007/978-3-030-45756-3_8
Pereira, Á. L. E. (2022) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.17.2022.tde-08082022-101746
Loss of MC1R signaling implicates TBX3 in pheomelanogenesis and melanoma predispositionPreprint
Berns, H. M., Watkins‐Chow, D. E., Lu, S., Louphrasitthiphol, P., Zhang, T., Brown, K. M., Moura‐Alves, P., Goding, C. R., & Pavan, W. J. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.03.10.532018
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“SOX10 regulates PD-L1 expression through a pathway including IRF4, a pigmentation-associated gene (27,28).”
BackgroundUncovering the genetic drivers of cutaneous melanoma and its risk factors
Ingold, N. (2024) · Queensland University of Technology · doi:10.5204/thesis.eprints.247498
Sobhiafshar, U., Çakici, B., Yilmaz, E., Ayhan, N. Y., Hedaya, L., Ayhan, M. C., Yerinde, C., Alankus, Y. B., Gürkaşlar, H. K., Firat‐Karalar, E. N., et al. (2024) · Molecular Oncology · doi:10.1002/1878-0261.13672 · Cited by 1
“This heterogeneity can at least partially be explained by the status of upstream regulators of IRF4 and by the particular genotypic variation at the functional SNP that regulates the melanocyte-specific intronic enhancer of IRF4 via these regulators [15].”
BackgroundMethodInfluentialda Silva, H. A. F. (2024) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/d.59.2024.tde-05042024-084356
Moazed, K. T. (2024) · Springer eBooks · doi:10.1007/978-3-031-64322-4_4
Functional enhancers: concept, screening, and validation
Lin, H., Chen, F., & Huang, J. (2025) · Scientia Sinica Vitae · doi:10.1360/ssv-2025-0113
McEwan, A. R., Rattray, A., Hutchings, G., Hay, E. A., Murgatroyd, C., & MacKenzie, A. (2025) · FEBS Journal · doi:10.1111/febs.70174
“Many excellent examples have been published that include the use of these technologies to determine the effects of disease-associated allelic variation on TF-DNA interactions [39 – 41].”
Genetic Background Predicts Uveal Melanoma Patients’ Outcomes
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“18,19 Strikingly, HERC2 rs12913832 is solely associated with a risk for M3 UM, whereas IRF4 rs12203592 is solely associated with a risk for D3 UM.”
InfluentialThe molecular puzzle of autoinflammatory skin diseases—a review of chosen conditions
Pieniawska, M., Rassek, K., Stein, T., Polańska, A., Dańczak‐Pazdrowska, A., & Iżykowska, K. (2025) · Journal of Applied Genetics · doi:10.1007/s13353-025-01019-6
Zhang, L., Tie, X., Che, F., Wang, G., Ge, Y., Li, B., & Yang, Y. (2024) · Figshare · doi:10.6084/m9.figshare.26596382
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UK Biobank Eye and Vision Consortium (2026) · Research Explorer (The University of Manchester)
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Laurette, P. (2016) · theses.fr (ABES) · doi:10.70675/b22b69c4z85a0z409czaccczc882ea46e923
Caractérisation du rôle de GAB2 et MITF dans les cellules de mélanome
Kim-Penard, H.-Y. (2019) · theses.fr (ABES) · doi:10.70675/5d393d17z0891z41e1zb35az0913c3882eec
Functional genomics characterization of genetic predisposing factors in uveal melanoma
Derrien, A. (2021) · theses.fr (ABES) · doi:10.70675/a794a7dfz4352z46f0zb97az064f9ea78e46
Uveal melanoma genetic predisposing factors
Verrier, T. (2025) · theses.fr (ABES) · doi:10.70675/af2c121az9a07z49e5z831dzd893d85bef70
Recognizing Physiologic Pigmentation in Skin of Color: A Narrative Review
Quiñonez, R. L., Masood, M., Rodrigues, M. A., Elbuluk, N., & Mohammad, T. F. (2026) · Pigment International · doi:10.4103/pigmentinternational_28_25
Su, Y., Liu, C., Lu, X., Chuang, H.-Y., Li, G., Shao, S., Kong, Y., Lee, J. W., Ng, R. H., Wong, S., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-71349-4 · Cited by 14
“Enriched TFs included AP-2 paralogs, MEF2C, and IRF1/4, consistent with their known role to co-regulate melanocyte differentiation in parallel with MITF and SOX10 35 – 37 .”
Julian, T. H., Dou, H., Duan, J., Huang, J., Yoo, E. M., Green, D. J., Strange, A., Alhathli, E. M., Sperrin, M., Keane, P. A., et al. (2026) · Nature Cardiovascular Research · doi:10.1038/s44161-026-00815-5 · Cited by 2
“Again, several of these variants were in genes with key roles in pigmentation ( TYR , OCA2 , DCT and IRF4 ) 19 .”
Ingold, N., Zhu, G., Duffy, D. L., Mothershaw, A., Martin, N. G., MacGregor, S., & Law, M. H. (2026) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.70100
“…( IRF4; genome-wide significant for flat nevus count ; also associated with lighter skin, blue eyes and increased freckles; Han et al. 2008; Praetorius et al. 2013) had a large positive effect on flat nevus count compared to a much smaller negative effect on raised and atypical nevi counts.”
The AHR–TFAP2A axis regulates melanosome transport by directly targeting myosin Va and Mlph
Sung, H.-Y., Jo, C. S., Hairu, Z., Baek, G. C., You, C. M., & Hwang, J. S. (2026) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2026.08.019
Zhang, H., Cao, F., Qian, J., Liu, E., Huang, Y., Zhang, X., Tang, K., & Guo, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1954595
“In melanocytes, the intronic variant rs12203592 regulates IRF4 expression through an enhancer mechanism and in fl uences tyrosinase-dependent pigmentation (47, 48).”
Metadata
- Authors
- Praetorius, C., Grill, C., Stacey, S. N., Metcalf, A. M., Gorkin, D. U., Robinson, K. C., Van Otterloo, E., Kim, R. S. Q., Bergsteinsdottir, K., Ogmundsdottir, M. H., Magnusdottir, E., Mishra, P. J., Davis, S. R., Guo, T., Zaidi, M. R., Helgason, A. S., Sigurdsson, M. I., Meltzer, P. S., Merlino, G., Petit, V., Larue, L., Loftus, S. K., Adams, D. R., Sobhiafshar, U., Emre, N. C. T., Pavan, W. J., Cornell, R., Smith, A. G., McCallion, A. S., Fisher, D. E., Stefansson, K., Sturm, R. A., & Steingrimsson, E.
- Affiliations
- University of Iceland (IS)
- deCODE Genetics (Iceland) (IS)
- The University of Queensland (AU)
- Johns Hopkins University (US)
- Harvard University (US)
- National Institutes of Health (US)
- Institut Curie (FR)
- Boğaziçi University (TR)
- University of Iowa (US)
- ORCID
- Praetorius, Christian
- Stacey, Simon N.
- Gorkin, David U.
- Robinson, Kathleen C.
- Ogmundsdottir, Margret H.
- Davis, Sean R.
- Guo, Theresa
- Zaidi, M. Raza
- Helgason, Agnar S.
- Sigurdsson, Martin I.
- Meltzer, Paul S.
- Merlino, Glenn
- Larue, Lionel
- Loftus, Stacie K.
- Adams, David R.
- Sobhiafshar, Ulduz
- Emre, N.C. Tolga
- Pavan, William J.
- Cornell, Robert
- Smith, Aaron G.
- McCallion, Andrew S.
- Fisher, David E.
- Sturm, Richard A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 155
- Issue
- 5
- Pages
- 1022-1033
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3873608
- OpenAlex
- W2034575591
- Cited by
- 228
- References
- 67
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 17 · 2023: 17 · 2022: 22 · 2021: 18 · 2020: 22 · 2019: 15 · 2018: 22 · 2017: 20 · 2016: 13 · 2015: 18 · 2014: 16 · 2013: 1
- FWCI
- 9.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ORBi (University of Liège) (submittedVersion, other-oa)
- Funders
- National Science Foundation
- Melanoma Research Alliance
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Háskóli Íslands
- Institut National Du Cancer
- National Institutes of Health
- National Cancer Institute (K22CA163799, P01CA163222)
- National Institute of General Medical Sciences (GM071648, T32GM007814, R01GM071648)
- National Institute of Neurological Disorders and Stroke (R01NS062972, NS062972)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR062547, R01AR043369)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- IRF4, melanogenesis, skin pigmentation, tyrosinase, MITF, TFAP2A, transcriptional regulation, sun sensitivity, freckles, eye color, hair color, gene regulatory networks, zebrafish, mice
- MeSH terms
- Interferon Regulatory Factor-4, Animals, Base Sequence, Enhancer Elements, Genetic, Humans, Melanocytes, Molecular Sequence Data, Pigmentation, Zebrafish, Signal Transduction, Polymorphism, Single Nucleotide, Transcription Factor AP-2, Interferon Regulatory Factors, Mice
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