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 is the transcription factor known as the 'master regulator of melanogenesis' due to its ability to activate many melanocyte-specific genes.
“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
The intronic IRF4 variant rs12203592 influences skin pigmentation, tanning response, and hair pigmentation, but shows weaker evolutionary signals than the major sweep loci.
“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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Global skin colour prediction from DNA
Walsh, S., Chaitanya, L., Breslin, K., Muralidharan, C., Bronikowska, A., Pośpiech, E., Koller, J., Kovatsi, L., Wollstein, A., Branicki, W., et al. (2017) · Human Genetics · doi:10.1007/s00439-017-1808-5 · Cited by 159 · see citing works
An Unexpectedly Complex Architecture for Skin Pigmentation in Africans
Martin, A. R., Lin, M., Granka, J. M., Myrick, J. W., Liu, X., Sockell, A., Atkinson, E. G., Werely, C. J., Möller, M., Sandhu, M. S., et al. (2017) · Cell · doi:10.1016/j.cell.2017.11.015 · Cited by 156 · see citing works
The Genetics of Human Skin and Hair Pigmentation.
Pavan, W., & Sturm, R. (2019) · Annual review of genomics and human genetics (Print) · doi:10.1146/annurev-genom-083118-015230 · Cited by 141 · see citing works
“Transcription factor AP-2α (TFAP2A) and MITF directly regulate IRF4 expression, and TYR expression depends on the IRF4 protein (28, 123).”
BackgroundGuo, J., Tao, H., Li, P., Li, L., Zhong, T., Wang, L., Ma, J., Chen, X., Song, T., & Zhang, H. (2018) · Scientific Reports · doi:10.1038/s41598-018-28719-w · Cited by 147 · see citing works
The biology of human hair greying
O’Sullivan, J. D. B., Nicu, C., Picard, M. A., Chéret, J., Bedogni, B., Tobin, D. J., & Paus, R. (2020) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12648 · Cited by 144 · see citing works
“Since IRF4 and MITF act cooperatively to activate transcription of tyrosinase (TYR) in cultured human melanoma cells (Praetorius et al., 2013), this presumptive driver of human greying (Adhikari et al., 2016) would be associated with reduced tyrosinase activity in the HFPU, rather than in MSC…”
BackgroundChahal, H. S., Lin, Y., Ransohoff, K. J., Hinds, D. A., Wu, W., Dai, H., Qureshi, A. A., Li, W., Kraft, P., Tang, J. Y., et al. (2016) · Nature Communications · doi:10.1038/ncomms12048 · Cited by 140 · see citing works
Genome-wide study of hair colour in UK Biobank explains most of the SNP heritability
Morgan, M. D., Pairo‐Castineira, E., Rawlik, K., Canela‐Xandri, O., Rees, J., Sims, D., Tenesa, A., & Jackson, I. J. (2018) · Nature Communications · doi:10.1038/s41467-018-07691-z · Cited by 133 · see citing works
Byun, J., Han, Y., Li, Y., Xia, J., Long, E., Choi, J., Xiao, X., Zhu, M., Zhou, W., Sun, R., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01115-x · Cited by 113 · see citing works
Sun‐induced freckling: ephelides and solar lentigines
Praetorius, C., Sturm, R. A., & Steingrı́msson, E. (2014) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12232 · Cited by 118 · see citing works
“Recently, the effects of IRF4 on pigmentation have been shown to be due to the rs12203592 polymorphism, which affects binding of the TFAP2A and MITF transcription factors to a regulatory element in intron 4 of IRF4, thus reducing IRF4 expression (Praetorius et al., 2013).”
BackgroundSeberg, H., Otterloo, E. V., & Cornell, R. A. (2017) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12611 · Cited by 113 · see citing works
“Similarly, TFAP2A and MITF cooperatively regulate the activity of a melanocyte- specific enhancer of IRF4 (Praetorius et al., 2013).”
InfluentialAcetyl-CoA Synthetase 2: A Critical Linkage in Obesity-Induced Tumorigenesis in Myeloma
Li, Z., Liu, H., He, J., Wang, Z., Yin, Z., You, G., Wang, Z., Davis, R. E., Lin, P., Bergsagel, P. L., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2020.12.011 · Cited by 108 · see citing works
“We next asked whether the regulation of IRF4 by ACSS2 is a common mechanism in other tumors, such as melanoma, in which IRF4 is also expressed and may act as a critical factor in melanoma growth (Praetorius et al., 2013; Seberg et al., 2017).”
BackgroundHeilmann‐Heimbach, S., Herold, C., Hochfeld, L. M., Hillmer, A. M., Nyholt, D. R., Hecker, J., Javed, A., Chew, E. G. Y., Pechlivanis, S., Drichel, D., et al. (2017) · Nature Communications · doi:10.1038/ncomms14694 · Cited by 101 · see citing works
Genetic Study of Complex Diseases in the Post-GWAS Era
Huang, Q. (2015) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2015.02.001 · Cited by 97 · see citing works
The Peripheral Clock Regulates Human Pigmentation
Hardman, J. A., Tobin, D. J., Haslam, I. S., Farjo, N. P., Farjo, B., Al‐Nuaimi, Y., Grimaldi, B., & Paus, R. (2014) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.442 · Cited by 96 · see citing works
“, 2013; see Supplementary Table S1) including the rate-limiting enzyme tyrosinase and microphthalmia-associated transcription factor (MITF) the ‘‘master regulator’’ of both melanogenesis and melanocyte biology, which leads to the transcription of tyrosinase (Du et al., 2003; Vachtenheim and Borovanský, 2010; Pogenberg…”
BackgroundIdentification of Susceptibility Loci for Cutaneous Squamous Cell Carcinoma
Asgari, M. M., Wang, W., Ioannidis, N. M., Itnyre, J., Hoffmann, T. J., Jorgenson, E., & Whittemore, A. S. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.01.013 · Cited by 94 · see citing works
“These include nonsynonymous SNPs in SLC45A2 on chromosome 5p13 and in TYR on chromosome 11q14, and a functional intronic SNP in IRF4 on chromosome 6p25.”
BackgroundInfluentialTFAP2 paralogs regulate melanocyte differentiation in parallel with MITF
Seberg, H. E., Van Otterloo, E., Loftus, S. K., Liu, H., Bonde, G., Sompallae, R., Gildea, D. E., Santana, J. F., Manak, J. R., Pavan, W. J., et al. (2017) · PLOS Genetics · doi:10.1371/journal.pgen.1006636 · Cited by 85 · see citing works
“both proteins regulate expression of CDKN1A/p21 [41,42] and IRF4 [37].”
BackgroundInfluentialSelf-citationZhang, T.-W., Choi, J., Kovacs, M. A., Shi, J.-X., Xu, M., Program, N., Goldstein, A., Trower, A. J., Bishop, D., Iles, M., et al. (2017) · bioRxiv · doi:10.1101/gr.233304.117 · Cited by 75 · see citing works
“A recent functional study identified rs12203592 as a functional variant regulating IRF4 expression through allele-specific binding of TFAP2A and mediating pigmentation phenotype via regulation of the melanin synthesis enzyme, TYR (Praetorius et al. 2013). rs12203592 is a cis-eQTL for IRF4 in several other tissues in G…”
BackgroundResultInfluentialBoddicker, R. L., Kip, N. S., Xing, X., Zeng, Y., Yang, Z., Lee, J., Almada, L. L., Elsawa, S. F., Knudson, R. A., Law, M. E., et al. (2015) · Blood · doi:10.1182/blood-2014-05-578575 · Cited by 83 · see citing works
“rs12203592-T has been associated with risk of childhood acute lymphoblastic leukemia and pigmentation inmelanocytes but has not been found to be associated with NHL risk.(18,65,66) Our data do not establish whether these genetic findings directly contribute to IRF4 expression in PTCLs.”
BackgroundA direct link between MITF, innate immunity, and hair graying
Harris, M. L., Fufa, T., Palmer, J. W., Joshi, S. S., Larson, D. M., Incao, A. A., Gildea, D. E., Trivedi, N. S., Lee, A. N., Day, C., et al. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2003648 · Cited by 77 · see citing works
New basal cell carcinoma susceptibility loci
Stacey, S., Helgason, H., Gudjonsson, S. A., Þorleifsson, G., Zink, F., Sigurðsson, Á., Kehr, B., Guðmundsson, J., Sulem, P., Sigurgeirsson, B., et al. (2015) · Nature Communications · doi:10.1038/ncomms7825 · Cited by 72 · see citing works
Visser, M., Palstra, R.-J. T. S., & Kayser, M. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu289 · Cited by 72 · see citing works
Using zebrafish to study skeletal genomics
Kwon, R. Y., Watson, C. J., & Karasik, D. (2019) · Bone · doi:10.1016/j.bone.2019.02.009 · Cited by 67 · see citing works
“[84] assayed the sequence containing rs12203592 using transgenic zebrafish by engineering a vector containing an intronic sequence for human IRF4 upstream of a minimal promoter and the GFP gene.”
IRF4 and IRF8: Governing the virtues of B Lymphocytes
Shukla, V., & Lu, R.-Q. (2014) · Frontiers in Biology · doi:10.1007/s11515-014-1318-y · Cited by 61 · see citing works
Genome-Wide Association Shows that Pigmentation Genes Play a Role in Skin Aging
Law, M. H., Medland, S. E., Zhu, G., Yazar, S., Viñuela, A., Wallace, L. M., Shekar, S. N., Duffy, D. L., Bataille, V. A., Glass, D., et al. (2017) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2017.04.026 · Cited by 63 · see citing works
Shades of complexity: New perspectives on the evolution and genetic architecture of human skin
Quillen, E. E., Norton, H. L., Parra, E. J., Lona‐Durazo, F., Ang, K. C., Illiescu, F. M., Pearson, L. N., Shriver, M. D., Lasisi, T., Gokcumen, O., et al. (2019) · American Journal of Physical Anthropology · doi:10.1002/ajpa.23737 · Cited by 67 · see citing works
“…a transcription factor with no known role in melanocyte biology, is associated with pale skin, eyes, and brown hair; this variant alters transcription factor binding of MITF (melanocyte master regulator), which in turn modulates pigmentation by altering TYR expression (Praetorius et al., 2013).”
BackgroundSOX10 Regulates Melanoma Immunogenicity through an IRF4–IRF1 Axis
Yokoyama, S., Takahashi, A., Kikuchi, R., Nishibu, S., Lo, J. A., Hejna, M., Moon, W. M., Kato, S., Zhou, Y., Hodi, F. S., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-2078 · Cited by 62 · see citing works
Visser, M., Palstra, R.-J., & Kayser, M. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv029 · Cited by 57 · see citing works
“When the rs12203592T-allele is present, TFAP2α-binding is reduced,which in turn leads toadecreasedexpressionof IRF4 (11).”
BackgroundResultInfluentialBallotti, R., Chéli, Y., & Bertolotto, C. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01290-7 · Cited by 60 · see citing works
Wang, L., Yao, Z. Q., Moorman, J. P., Xu, Y., & Ning, S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0106788 · Cited by 57 · see citing works
Yu, L., Gao, Z., Xu, Q., Pan, X., & Xiao, Y. (2022) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2022.114320 · Cited by 54 · see citing works
IRF4, MC1R and TYR genes are risk factors for actinic keratosis independent of skin color
Jacobs, L. C., Liu, F., Pardo, L. M., Albert Hofman, D., Uitterlinden, A. G., Kayser, M., & Nijsten, T. E. C. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv076 · Cited by 53 · see citing works
“Decreased expression of IRF4 will decrease expression of TYR, a key enzyme in the rate ofmelanin synthesis (24).”
Parkinson-Associated SNCA Enhancer Variants Revealed by Open Chromatin in Mouse Dopamine Neurons
McClymont, S. A., Hook, P. W., Soto, A. I., Reed, X., Law, W., Kerans, S. J., Waite, E. L., Briceno, N., Thole, J. F., Heckman, M. G., et al. (2018) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2018.10.018 · Cited by 50 · see citing works
Fufa, T., Harris, M. L., Watkins‐Chow, D. E., Levy, D. J., Gorkin, D. U., Gildea, D. E., Song, L., Safi, A., Crawford, G. E., Sviderskaya, E. V., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv267 · Cited by 51 · see citing works
Skin Pigmentation Genetics for the Clinic
Ainger, S. A., Jagirdar, K., Lee, K., Soyer, H. P., & Sturm, R. A. (2017) · Dermatology · doi:10.1159/000468538 · Cited by 50 · see citing works
The Evolutionary History of Human Skin Pigmentation
Rocha, J. (2019) · Journal of Molecular Evolution · doi:10.1007/s00239-019-09902-7 · Cited by 50 · see citing works
Goat Genomic Resources: The Search for Genes Associated with Its Economic Traits
Siddiki, A. Z., Miah, G., Islam, M. S., Kumkum, M., Rumi, M. H., Baten, A., & Hossain, M. A. (2020) · International Journal of Genomics · doi:10.1155/2020/5940205 · Cited by 49 · see citing works
Precision medicine driven by cancer systems biology
Filipp, F. V. (2017) · Cancer and Metastasis Reviews · doi:10.1007/s10555-017-9662-4 · Cited by 48 · see citing works
Molecular mechanisms underlying noncoding risk variations in psychiatric genetic studies
Xiao, X., Chang, H., & Li, M. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.241 · Cited by 47 · see citing works
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Aponte, J. L., Chiano, M. N., Yerges-Armstrong, L. M., Hinds, D. A., Tian, C., Gupta, A., Guo, C., Fraser, D. J., Freudenberg, J., Rajpal, D. K., et al. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy184 · Cited by 46 · see citing works
“IRF4 plays a role in the initiation and progression of autoimmune diseases (32) such as celiac disease (33) and is strongly associated with human pigmentation traits (34).”
BackgroundSarin, K. Y., Lin, Y., Daneshjou, R., Ziyatdinov, A., Þorleifsson, G., Rubin, A. J., Pardo, L. M., Wu, W., Khavari, P. A., Uitterlinden, A. G., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14594-5 · Cited by 46 · see citing works
Liu, F., Qu, L., Li, H., He, J., Wang, L., Fang, Y., Yan, X., Yang, Q., Peng, B., Wu, W., et al. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14112308 · Cited by 44 · see citing works
Jiang, M. (2016) · Tumor Biology · doi:10.1007/s13277-016-5301-x · Cited by 43 · see citing works
“MITFactivation stimulates the expression of tyrosinase, an essential enzyme inmelanin synthesis [115].”
BackgroundPośpiech, E., Kukla‐Bartoszek, M., Karłowska-Pik, J., Zieliński, P., Woźniak, A., Boroń, M., Dąbrowski, M., Zubańska, M., Jarosz, A., Grzybowski, T., et al. (2020) · BMC Genomics · doi:10.1186/s12864-020-06926-y · Cited by 42 · see citing works
Orlow, I., Satagopan, J. M., Berwick, M., Enriquez, H. L., White, K. A., Cheung, K., Dusza, S. W., Oliveria, S. A., Marchetti, M. A., Scope, A., et al. (2014) · British Journal of Dermatology · doi:10.1111/bjd.13467 · Cited by 41 · see citing works
Bhatia, S., & Kleinjan, D. A. (2014) · Human Genetics · doi:10.1007/s00439-014-1424-6 · Cited by 41 · see citing works
TFAP2 paralogs facilitate chromatin access for MITF at pigmentation and cell proliferation genes
Kenny, C., Dilshat, R., Seberg, H., Otterloo, E. V., Bonde, G., Helverson, A., Franke, C. M., Steingrı́msson, E., & Cornell, R. A. (2022) · PLoS Genetics · doi:10.1371/journal.pgen.1010207 · Cited by 39 · see citing works
“How MITF and TFAP2 cooperate to regulate these cellular processes is largely unknown.”
BackgroundInfluentialGibbs, D. C., Orlow, I., Bramson, J. I., Kanetsky, P. A., Luo, L., Kricker, A., Armstrong, B. K., Anton‐Culver, H., Gruber, S. B., Marrett, L. D., et al. (2016) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djw004 · Cited by 38 · see citing works
“Within the large international population-based Genes, Environment, and Melanoma (GEM) Study, we previously investigated 47 single-nucleotide polymorphisms (SNPs) in 21 of these putative low-penetrance melanoma susceptibility loci and found variants in the TERT, TYRP1, MTAP, TYR, NCOA6, and MX2 gene regions and a PARP…”
BackgroundInfluentialNew insights into genetics underlying of plumage color
Davoodi, P., Ehsani, A., Torshizi, R. V., & Masoudi, A. A. (2021) · Animal Genetics · doi:10.1111/age.13156 · Cited by 38 · see citing works
Hook, P. W., & McCallion, A. S. (2020) · Genome Research · doi:10.1101/gr.256578.119 · Cited by 33 · see citing works
“Previously, we have successfully used mouse chromatin data to prioritize common human variants for pigmentation and Parkinson disease (Praetorius et al. 2013; McClymont et al. 2018).”
MethodMadelaine, R., Notwell, J. H., Skariah, G. M., Halluin, C., Chen, C. C., Bejerano, G., & Mourrain, P. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky166 · Cited by 32 · see citing works
Analysis of the genetic loci of pigment pattern evolution in vertebrates
Elkin, J., Martin, A., Courtier‐Orgogozo, V., & Santos, M. E. (2023) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12952 · Cited by 35 · see citing works
Hernando, B., Ibáñez, M. V., Deserio-Cuesta, J. A., Soria‐Navarro, R., Sastre, I. V., & Martínez‐Cadenas, C. (2017) · Forensic Science International Genetics · doi:10.1016/j.fsigen.2017.11.013 · Cited by 34 · see citing works
pH‐controlled histone acetylation amplifies melanocyte differentiation downstream of MITF
Raja, D. A., Gotherwal, V., Burse, S. A., Subramaniam, Y. J., Sultan, F., Vats, A., Gautam, H., Sharma, B., Sharma, S., Singh, A. K., et al. (2019) · EMBO Reports · doi:10.15252/embr.201948333 · Cited by 34 · see citing works
“A key challenge still is to selectively activate certain gene modules dynamically, while maintaining other effector functions of MITF [9,12].”
Genetic variation in regulatory DNA elements: the case of OCA 2 transcriptional regulation
Visser, M., Kayser, M., Grosveld, F. G., & Palstra, R.-J. T. S. (2014) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12210 · Cited by 35 · see citing works
“…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).”
BackgroundHuman Hair Graying Revisited: Principles, Misconceptions, and Key Research Frontiers
Paus, R., Sevilla, A., & Grichnik, J. M. (2023) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2023.09.276 · Cited by 39 · see citing works
Deane‐Coe, P. E., Chu, E. T., Slavney, A., Boyko, A. R., & Sams, A. J. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007648 · Cited by 34 · see citing works
Merecz-Sadowska, A., Sitarek, P., Kowalczyk, T., Zajdel, K., Kucharska, E., & Zajdel, R. (2022) · Molecules · doi:10.3390/molecules27144360 · Cited by 34 · see citing works
“Many genes that encode diverse proteins are implicated in different steps of pigmentation such as melanocyte formation from the neural crest, formation of melanosome components, pigment inclusion, and the transfer of melanosomes from melanocytes to keratinocytes [23].”
BackgroundHölzel, M., Landsberg, J., Glodde, N., Bald, T., Rogava, M., Riesenberg, S., Becker, A. J., Jonsson, G. G., & Tüting, T. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-1090 · Cited by 33 · see citing works
Tfap2b specifies an embryonic melanocyte stem cell that retains adult multifate potential
Brombin, A., Simpson, D. J., Trávníčková, J., Brunsdon, H., Zeng, Z., Lu, Y., Young, A. I. J., Chandra, T., & Patton, E. E. (2022) · Cell Reports · doi:10.1016/j.celrep.2021.110234 · Cited by 32 · see citing works
Taylor, D. J., Ballinger, M. J., Zhan, J. J., Hanzly, L. E., & Bruenn, J. A. (2014) · PeerJ · doi:10.7717/peerj.556 · Cited by 32 · see citing works
Hong, J., Li, S., Wang, X., Mei, C., & Zan, L. (2018) · Bioscience Reports · doi:10.1042/bsr20181705 · Cited by 30 · see citing works
Markiewicz, E., & Idowu, O. C. (2020) · Clinical Cosmetic and Investigational Dermatology · doi:10.2147/ccid.s245043 · Cited by 33 · see citing works
Somatic mutations in facial skin from countries of contrasting skin cancer risk
King, C., Fowler, J. C., Abnizova, I., Sood, R. K., Hall, M., Szeverényi, I., Tham, M., Huang, J., Young, S. M., Hall, B. A., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01468-x · Cited by 31 · see citing works
“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 .”
BackgroundRecent omics advances in hair aging biology and hair biomarkers analysis
Adav, S. S., & Ng, K. W. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102041 · Cited by 31 · see citing works
Feng, Y., Xie, N., Inoue, F., Fan, S., Saskin, J., Zhang, C., Zhang, F., Hansen, M. E. B., Nyambo, T., Mpoloka, S. W., et al. (2024) · Nature Genetics · doi:10.1038/s41588-023-01626-1 · Cited by 31 · see citing works
“Additionally, only a few of the candidate variants associated with human skin pigmentation have been thoroughly investigated through functional experiments 14–17 .”
Norton, H. L., Edwards, M., Krithika, S., Johnson, M., Werren, E. A., & Parra, E. J. (2016) · American Journal of Physical Anthropology · doi:10.1002/ajpa.22861 · Cited by 30 · see citing works
Ma, X., Jiao, X., Ma, Z., & Hejtmancik, J. F. (2016) · Scientific Reports · doi:10.1038/srep23206 · Cited by 30 · see citing works
Meyer, O., Lunn, M. M. B., Garcia, S. L., Kjærbye, A. B., Morling, N., Børsting, C., & Andersen, J. D. (2020) · PLoS ONE · doi:10.1371/journal.pone.0239131 · Cited by 20 · see citing works
“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].”
InfluentialLee, W., Shen, S., Wu, P., Chou, C., Shih, Y., Yeh, C., Yeh, K., & Jiang, M. (2015) · Molecular Carcinogenesis · doi:10.1002/mc.22407 · Cited by 30 · see citing works
Chhabra, Y., Yong, X. L. H., Fane, M. E., Soogrim, A., Lim, W., Mahiuddin, D. N., Kim, R. S. Q., Ashcroft, M. M., Beatson, S. A., Ainger, S. A., et al. (2017) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12620 · Cited by 28 · see citing works
“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.”
BackgroundResultInfluentialGWAS Analysis of 17,019 Korean Women Identifies the Variants Associated with Facial Pigmented Spots
Shin, J., Leem, S., Kim, B., Kim, Y., Lee, S., Song, H. J., Seo, J. Y., Park, S. G., Won, H., & Kang, N. G. (2020) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2020.08.007 · Cited by 26 · see citing works
Parks, R., Kim, C. J., Al-Safi, Z. A., Armstrong, A. A., Zore, T., & Moatamed, N. A. (2018) · International Journal of Surgical Pathology · doi:10.1177/1066896918814307 · Cited by 24 · see citing works
Molecular and biochemical mechanisms of human iris color: A comprehensive review
Dorgaleleh, S., Naghipoor, K., Barahouie, A., Dastaviz, F., & Oladnabi, M. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29824 · Cited by 23 · see citing works
“TYR expression was reduced to 50%, but SLC45A2, SLC24A5, and DCT remained unaffected (Praetorius et al., 2013).”
BackgroundWhole Genome Resequencing Reveals Selection Signals Related to Wool Color in Sheep
Zhang, W., Jin, M., Lu, Z., Li, T., Wang, H., Yuan, Z., & Wei, C. (2023) · Animals · doi:10.3390/ani13203265 · Cited by 23 · see citing works
“Variations in IRF4 lead to lighter coloration [31,32].”
BackgroundBromodomain and extra-terminal domain (BET) proteins regulate melanocyte differentiation
Trivedi, A. R., Mehrotra, A., Baum, C. E., Lewis, B., Basuroy, T., Blomquist, T. M., Trumbly, R. J., Filipp, F. V., Setaluri, V., & de la Serna, I. L. (2020) · Epigenetics & Chromatin · doi:10.1186/s13072-020-00333-z · Cited by 22 · see citing works
Zhang, T., Choi, J., Dilshat, R., Einarsdottir, B. O., Kovacs, M. A., Xu, M., Malasky, M., Chowdhury, S., Jones, K. M., Bishop, D. T., et al. (2021) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2021.06.018 · Cited by 20 · see citing works
“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…”
BackgroundLucock, M. D., Jones, P. R., Veysey, M. J., Thota, R. N., Garg, M. L., Furst, J. E., Martin, C., Yates, Z. R., Scarlett, C. J., Jablonski, N. G., et al. (2021) · American Journal of Human Biology · doi:10.1002/ajhb.23667 · Cited by 22 · see citing works
Selection signatures for fiber production in commercial species: A review
Ghildiyal, K., Panigrahi, M., Kumar, H., Rajawat, D., Nayak, S. S., Lei, C., Bhushan, B., & Dutt, T. (2022) · Animal Genetics · doi:10.1111/age.13272 · Cited by 23 · see citing works
Tang, H., & Chen, C. Y. (2015) · SpringerPlus · doi:10.1186/s40064-015-0956-0 · Cited by 22 · see citing works
Wei, W., Viatte, S., Merriman, T. R., Barton, A. C., & Worthington, J. (2017) · Scientific Reports · doi:10.1038/s41598-017-05447-1 · Cited by 21 · see citing works
Wang, L., Xia, Y., Chen, Y., Dai, R., Qiu, W., Meng, Q., Kuney, L., & Chen, C. (2019) · Genomics Proteomics & Bioinformatics · doi:10.1016/j.gpb.2019.02.002 · Cited by 23 · see citing works
A large Canadian cohort provides insights into the genetic architecture of human hair colour
Lona‐Durazo, F., de Aquino, M. M., Thakur, R., Funderburk, K. M., Zhang, T., Kovacs, M. A., Choi, J., Brown, K. M., & Parra, E. J. (2021) · Communications Biology · doi:10.1038/s42003-021-02764-0 · Cited by 22 · see citing works
Kim, Y., Yin, J., Huang, H., Jorgenson, E., Choquet, H., & Asgari, M. M. (2022) · Communications Biology · doi:10.1038/s42003-022-03301-3 · Cited by 24 · see citing works
Forensic DNA Phenotyping: Genes and Genetic Variants for Eye Color Prediction
Brancato, D., Coniglio, E., Bruno, F., Agostini, V., Saccone, S., & Federico, C. (2023) · Genes · doi:10.3390/genes14081604 · Cited by 22 · see citing works
“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].”
BackgroundSkin colour: A window into human phenotypic evolution and environmental adaptation
Liu, J., Bitsue, H. K., & Yang, Z. (2024) · Molecular Ecology · doi:10.1111/mec.17369 · Cited by 25 · see citing works
“Within this pathway, the melanocyte-inducing transcription factor ( MITF ) acts as a key transcription factor, predominantly governing the expression levels of TYR and TYRP1 , and thus influencing melanin production (Praetorius et al., 2013).”
BackgroundVariation in Hsp70-1A Expression Contributes to Skin Color Diversity
Murase, D., Hachiya, A., Fullenkamp, R., Beck, A., Moriwaki, S., Hase, T., Takema, Y., & Manga, P. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.03.038 · Cited by 21 · see citing works
“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).”
BackgroundProgram, N. C. S., Fufa, T., Baxter, L. L., Wedel, J. C., Gildea, D. E., Loftus, S. K., & Pavan, W. J. (2019) · Epigenetics & Chromatin · doi:10.1186/s13072-019-0297-2 · Cited by 22 · see citing works
“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…”
BackgroundSH3BP4, 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 · see citing works
- 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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