A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway

Christian Praetorius; Christine Grill; Simon N. Stacey; Alexander M. Metcalf; David U. Gorkin; Kathleen C. Robinson; Eric Van Otterloo; Reuben S.Q. Kim; Kristin Bergsteinsdottir; Margret H. Ogmundsdottir; Erna Magnusdottir; Pravin J. Mishra; Sean Davis; Theresa Guo; M. Raza Zaidi; Agnar S. Helgason; Martin I. Sigurdsson; Paul Meltzer; Glenn Merlino; Valérie Petit; Lionel Larue; Stacie K. Loftus; David R. Adams; Ulduz Sobhiafshar; Tolga O. Bozkurt; William J. Pavan; Robert A. Cornell; Aaron G. Smith; Andrew S. McCallion; David E. Fisher; Kari Stefansson; Richard A. Sturm; Eirikur Steingrimsson

doi:10.1016/j.cell.2013.10.022

A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway

Christian Praetorius, Christine Grill, Simon N. Stacey, Alexander M. Metcalf, David U. Gorkin, Kathleen C. Robinson, Eric Van Otterloo, Reuben S.Q. Kim, Kristin Bergsteinsdottir, Margret H. Ogmundsdottir, Erna Magnusdottir, Pravin J. Mishra, Sean Davis, Theresa Guo, M. Raza Zaidi, Agnar S. Helgason, Martin I. Sigurdsson, Paul Meltzer, Glenn Merlino, Valérie PetitLionel Larue, Stacie K. Loftus, David R. Adams, Ulduz Sobhiafshar, Tolga O. Bozkurt, William J. Pavan, Robert A. Cornell, Aaron G. Smith, Andrew S. McCallion, David E. Fisher, Kari Stefansson, Richard A. Sturm, Eirikur Steingrimsson

Research output: Contribution to journal › Article › peer-review

178 Scopus citations

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.

Original language	English
Pages (from-to)	1022-33
Number of pages	12
Journal	Cell
Volume	155
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2013.10.022
State	Published - Nov 21 2013

Keywords

Animals
Base Sequence
Enhancer Elements, Genetic
Humans
Interferon Regulatory Factors/chemistry
Melanocytes/metabolism
Mice
Molecular Sequence Data
Pigmentation
Polymorphism, Single Nucleotide
Signal Transduction
Transcription Factor AP-2/chemistry
Zebrafish

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10.1016/j.cell.2013.10.022

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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., Guo, T., Zaidi, M. R., Helgason, A. S., Sigurdsson, M. I., Meltzer, P., Merlino, G., ... Steingrimsson, E. (2013). A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell, 155(5), 1022-33. https://doi.org/10.1016/j.cell.2013.10.022

@article{a074e17f3d9548f38d828ff166a4aee4,

title = "A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway",

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.",

keywords = "Animals, Base Sequence, Enhancer Elements, Genetic, Humans, Interferon Regulatory Factors/chemistry, Melanocytes/metabolism, Mice, Molecular Sequence Data, Pigmentation, Polymorphism, Single Nucleotide, Signal Transduction, Transcription Factor AP-2/chemistry, Zebrafish",

author = "Christian Praetorius and Christine Grill and Stacey, {Simon N.} and Metcalf, {Alexander M.} and Gorkin, {David U.} and Robinson, {Kathleen C.} and {Van Otterloo}, Eric and Kim, {Reuben S.Q.} and Kristin Bergsteinsdottir and Ogmundsdottir, {Margret H.} and Erna Magnusdottir and Mishra, {Pravin J.} and Sean Davis and Theresa Guo and Zaidi, {M. Raza} and Helgason, {Agnar S.} and Sigurdsson, {Martin I.} and Paul Meltzer and Glenn Merlino and Val{\'e}rie Petit and Lionel Larue and Loftus, {Stacie K.} and Adams, {David R.} and Ulduz Sobhiafshar and Bozkurt, {Tolga O.} and Pavan, {William J.} and Cornell, {Robert A.} and Smith, {Aaron G.} and McCallion, {Andrew S.} and Fisher, {David E.} and Kari Stefansson and Sturm, {Richard A.} and Eirikur Steingrimsson",

year = "2013",

month = nov,

day = "21",

doi = "10.1016/j.cell.2013.10.022",

language = "English",

volume = "155",

pages = "1022--33",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "5",

}

Praetorius, C, Grill, C, Stacey, SN, Metcalf, AM, Gorkin, DU, Robinson, KC, Van Otterloo, E, Kim, RSQ, Bergsteinsdottir, K, Ogmundsdottir, MH, Magnusdottir, E, Mishra, PJ, Davis, S, Guo, T, Zaidi, MR, Helgason, AS, Sigurdsson, MI, Meltzer, P, Merlino, G, Petit, V, Larue, L, Loftus, SK, Adams, DR, Sobhiafshar, U, Bozkurt, TO, Pavan, WJ, Cornell, RA, Smith, AG, McCallion, AS, Fisher, DE, Stefansson, K, Sturm, RA & Steingrimsson, E 2013, 'A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway', Cell, vol. 155, no. 5, pp. 1022-33. https://doi.org/10.1016/j.cell.2013.10.022

TY - JOUR

T1 - A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway

AU - Praetorius, Christian

AU - Grill, Christine

AU - Stacey, Simon N.

AU - Metcalf, Alexander M.

AU - Gorkin, David U.

AU - Robinson, Kathleen C.

AU - Van Otterloo, Eric

AU - Kim, Reuben S.Q.

AU - Bergsteinsdottir, Kristin

AU - Ogmundsdottir, Margret H.

AU - Magnusdottir, Erna

AU - Mishra, Pravin J.

AU - Davis, Sean

AU - Guo, Theresa

AU - Zaidi, M. Raza

AU - Helgason, Agnar S.

AU - Sigurdsson, Martin I.

AU - Meltzer, Paul

AU - Merlino, Glenn

AU - Petit, Valérie

AU - Larue, Lionel

AU - Loftus, Stacie K.

AU - Adams, David R.

AU - Sobhiafshar, Ulduz

AU - Bozkurt, Tolga O.

AU - Pavan, William J.

AU - Cornell, Robert A.

AU - Smith, Aaron G.

AU - McCallion, Andrew S.

AU - Fisher, David E.

AU - Stefansson, Kari

AU - Sturm, Richard A.

AU - Steingrimsson, Eirikur

PY - 2013/11/21

Y1 - 2013/11/21

N2 - 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.

AB - 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.

KW - Animals

KW - Base Sequence

KW - Enhancer Elements, Genetic

KW - Humans

KW - Interferon Regulatory Factors/chemistry

KW - Melanocytes/metabolism

KW - Mice

KW - Molecular Sequence Data

KW - Pigmentation

KW - Polymorphism, Single Nucleotide

KW - Signal Transduction

KW - Transcription Factor AP-2/chemistry

KW - Zebrafish

UR - http://www.scopus.com/inward/record.url?scp=84889578835&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2013.10.022

DO - 10.1016/j.cell.2013.10.022

M3 - Article

C2 - 24267888

SN - 0092-8674

VL - 155

SP - 1022

EP - 1033

JO - Cell

JF - Cell

IS - 5

ER -

A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway

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