Cited by 228melanin and skin pigmentationMelanoma and MAPK PathwaysGenetic Associations and Epidemiology

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A Polymorphism in IRF4 Affects Human Pigmentation through a Tyrosinase-Dependent MITF/TFAP2A Pathway

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Praetorius, Christian, Grill, Christine, Stacey, Simon N., Metcalf, Alexander M., Gorkin, David U., Robinson, Kathleen C., Van Otterloo, Eric, Kim, Reuben S.Q., Bergsteinsdottir, Kristin, Ogmundsdottir, Margret H., Magnusdottir, Erna, Mishra, Pravin J., Davis, Sean R., Guo, Theresa, Zaidi, M. Raza, Helgason, Agnar S., Sigurdsson, Martin I., Meltzer, Paul S., Merlino, Glenn, Petit, Valerie, 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., Stefansson, Kari, Sturm, Richard A., Steingrimsson, Eirikur·2013·Cell

DOI 10.1016/j.cell.2013.10.022PMC PMC3873608

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Abstract

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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TFAP2 paralogs facilitate chromatin access for MITF at pigmentation and cell proliferation genes
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Association of Interferon Regulatory Factor-4 Polymorphism rs12203592 With Divergent Melanoma Pathways
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“…for example, the cancer risk variant rs6983267 (Ahmadiyeh et al., 2010; Jia et al., 2009; Pomerantz et al., 2009), variants associated with coronary artery disease (Harismendy et al., 2010), and more recently for the pigment associated SNP rs12203592 within the IRF4 gene (Praetorius et al., 2013).”
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Human Hair Graying Revisited: Principles, Misconceptions, and Key Research Frontiers
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A Preclinical Model of Malignant Peripheral Nerve Sheath Tumor-like Melanoma Is Characterized by Infiltrating Mast Cells
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“For example, rs12203592 alters IRF4 levels and expression of the pigmentation enzyme encoded by TYR 32 . rs4778210, positively selected in Singapore-ans 33 , is adjacent to OCA2 , encoding a melanosomal anion channel that is essential for melanin synthesis 34 .”
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Recent omics advances in hair aging biology and hair biomarkers analysis
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“Additionally, only a few of the candidate variants associated with human skin pigmentation have been thoroughly investigated through functional experiments 14–17 .”
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“Variants in the IRF4 target region IRF4 has previously been shown to activate the expression of TYR through cooperation with the microphthalmia-associated transcription factor (MITF) [31].”
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“Higher TYR expression matched a higher activity based on the L-DOPA oxidation assays and can potentially explain the basis of rs12203592*T allele association with lighter pigmentation traits (Duffy et al., 2010b; Praetorius et al., 2013), solar lentigines (SL) (Laville et al.”
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“TYR expression was reduced to 50%, but SLC45A2, SLC24A5, and DCT remained unaffected (Praetorius et al., 2013).”
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“IRF4 is primarily known as an interferon regulatory factor highly expressed in lymphocytes and blood cells, but rs1220 3592 is located in a melanocyte-specific enhancer element and seems to be regulated through a melanocyte-lineage-specific transcriptional program affecting pigmentation phenotypes.(57) Consistent with…”
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“In particular, the rs12203592:C/T located in intron 4 acts as a melanocyte-specific enhancer element, and the rs12203592:T allele reduces its activity [70].”
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Background
Variation in Hsp70-1A Expression Contributes to Skin Color Diversity
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“Differing degrees of skin pigmentation observed among ethnic groups can also be partially attributed to differences in tyrosinase activity, some of which is accounted for by genetic variants at the TYR (Jagirdar et al., 2014) and IRF4 loci (Praetorius et al., 2013).”
Background
MEK inhibition remodels the active chromatin landscape and induces SOX10 genomic recruitment in BRAF(V600E) mutant melanoma cells
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“Several of these factors exhibit co-binding and/or regulation of one another during neural crest and melanocyte development; for example, ETS1 and SOX10 interact to promote proper melanocyte development [40, 99], TFAP2A and MITF interact to regulate pigmentation [54, 100], and SOX10 activates MITF, while MITF has been…”
Background
SH3BP4, a novel pigmentation gene, is inversely regulated by miR-125b and MITF
Kim, K., Lee, T. R., & Cho, E. (2017) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.115 · Cited by 21

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)
DOI: 10.1016/j.cell.2013.10.022
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 385 d)
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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A Polymorphism in IRF4 Affects Human Pigmentation through a Tyrosinase-Dependent MITF/TFAP2A Pathway

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