XA 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 R. Davis; Theresa Guo; M. Raza Zaidi; Agnar S. Helgason; Martin I. Sigurdsson; Paul S. Meltzer; Glenn Merlino; Valerie Petit; Lionel Larue; Stacie K. Loftus; David R. Adams; Ulduz Sobhiafshar; N. C.Tolga Emre; William J. Pavan; Robert 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

XA 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 R. Davis
, Theresa Guo
, M. Raza Zaidi
, Agnar S. Helgason
, Martin I. Sigurdsson
, Paul S. Meltzer
, Glenn Merlino
, Valerie Petit

Lionel Larue, Stacie K. Loftus, David R. Adams, Ulduz Sobhiafshar, N. C.Tolga Emre, William J. Pavan, Robert Cornell, Aaron G. Smith, Andrew S. McCallion, David E. Fisher, Kari Stefansson, Richard A. Sturm, Eirikur Steingrimsson

Háskóli Íslands, Landspítali

Rannsóknarafurð: Framlag til fræðitímarits › Grein › ritrýni

Útdráttur

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.

Upprunalegt tungumál	Enska
Síður (frá-til)	1022-1033
Fræðitímarit	Cell
Bindi	155
Númer tölublaðs	5
DOI	https://doi.org/10.1016/j.cell.2013.10.022
Útgáfustaða	Útgefið - 21 nóv. 2013

Athugasemd

Funding Information: We thank Thorunn Rafnar, Magnus Karl Magnusson, Unnur Thorsteinsdottir, Colin R. Goding, and Thorarinn Gudjonsson for critical comments on the manuscript. This work was supported by grants from NIH (5R01 AR043369-16), Melanoma Research Alliance, Dr. Miriam and Sheldon Adelson Medical Research Foundation, US-Israel Binational Science Foundation (to D.E.F.), Ligue Nationale Contre le Cancer (Equipe labellisée) and INCa (to L.L.), the Icelandic Research Fund and the Research Fund of the University of Iceland (to E.S.), the Haskolasjodur Student Fund (to E.S., C.P., and C.G.), the Jules Verne Fund (to E.S. and L.L.), by the National Institute of General Medical Sciences (GM071648) and National Institute of Neurological Disease and Stroke (NS062972; to A.S.M.), the National Human Genome Research Institute’s Intramural Research Program (to W.J.P. and S.L.), and an NSF Graduate Research Fellowship (to D.U.G.).

Aðgangur að skjali

10.1016/j.cell.2013.10.022

Vitna í þetta

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., ... Steingrimsson, E. (2013). XA polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell, 155(5), 1022-1033. https://doi.org/10.1016/j.cell.2013.10.022

@article{930bbb8c533b469682c174f10a3a090b,

title = "XA 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.",

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 Davis, \{Sean R.\} and Theresa Guo and Zaidi, \{M. Raza\} and Helgason, \{Agnar S.\} and Sigurdsson, \{Martin I.\} and Meltzer, \{Paul S.\} and Glenn Merlino and Valerie Petit and Lionel Larue and Loftus, \{Stacie K.\} and Adams, \{David R.\} and Ulduz Sobhiafshar and Emre, \{N. C.Tolga\} and Pavan, \{William J.\} and Robert Cornell and Smith, \{Aaron G.\} and McCallion, \{Andrew S.\} and Fisher, \{David E.\} and Kari Stefansson and Sturm, \{Richard A.\} and Eirikur Steingrimsson",

note = "Funding Information: We thank Thorunn Rafnar, Magnus Karl Magnusson, Unnur Thorsteinsdottir, Colin R. Goding, and Thorarinn Gudjonsson for critical comments on the manuscript. This work was supported by grants from NIH (5R01 AR043369-16), Melanoma Research Alliance, Dr. Miriam and Sheldon Adelson Medical Research Foundation, US-Israel Binational Science Foundation (to D.E.F.), Ligue Nationale Contre le Cancer (Equipe labellis{\'e}e) and INCa (to L.L.), the Icelandic Research Fund and the Research Fund of the University of Iceland (to E.S.), the Haskolasjodur Student Fund (to E.S., C.P., and C.G.), the Jules Verne Fund (to E.S. and L.L.), by the National Institute of General Medical Sciences (GM071648) and National Institute of Neurological Disease and Stroke (NS062972; to A.S.M.), the National Human Genome Research Institute{\textquoteright}s Intramural Research Program (to W.J.P. and S.L.), and an NSF Graduate Research Fellowship (to D.U.G.).",

year = "2013",

month = nov,

day = "21",

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

language = "English",

volume = "155",

pages = "1022--1033",

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, SR, Guo, T, Zaidi, MR, Helgason, AS , Sigurdsson, MI, Meltzer, PS, Merlino, G, Petit, V, Larue, L, Loftus, SK, Adams, DR, Sobhiafshar, U, Emre, NCT, Pavan, WJ, Cornell, R, Smith, AG, McCallion, AS, Fisher, DE, Stefansson, K, Sturm, RA & Steingrimsson, E 2013, 'XA polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway', Cell, bind. 155, nr. 5, bls. 1022-1033. https://doi.org/10.1016/j.cell.2013.10.022

TY - JOUR

T1 - XA 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 R.

AU - Guo, Theresa

AU - Zaidi, M. Raza

AU - Helgason, Agnar S.

AU - Sigurdsson, Martin I.

AU - Meltzer, Paul S.

AU - Merlino, Glenn

AU - Petit, Valerie

AU - Larue, Lionel

AU - Loftus, Stacie K.

AU - Adams, David R.

AU - Sobhiafshar, Ulduz

AU - Emre, N. C.Tolga

AU - Pavan, William J.

AU - Cornell, Robert

AU - Smith, Aaron G.

AU - McCallion, Andrew S.

AU - Fisher, David E.

AU - Stefansson, Kari

AU - Sturm, Richard A.

AU - Steingrimsson, Eirikur

N1 - Funding Information: We thank Thorunn Rafnar, Magnus Karl Magnusson, Unnur Thorsteinsdottir, Colin R. Goding, and Thorarinn Gudjonsson for critical comments on the manuscript. This work was supported by grants from NIH (5R01 AR043369-16), Melanoma Research Alliance, Dr. Miriam and Sheldon Adelson Medical Research Foundation, US-Israel Binational Science Foundation (to D.E.F.), Ligue Nationale Contre le Cancer (Equipe labellisée) and INCa (to L.L.), the Icelandic Research Fund and the Research Fund of the University of Iceland (to E.S.), the Haskolasjodur Student Fund (to E.S., C.P., and C.G.), the Jules Verne Fund (to E.S. and L.L.), by the National Institute of General Medical Sciences (GM071648) and National Institute of Neurological Disease and Stroke (NS062972; to A.S.M.), the National Human Genome Research Institute’s Intramural Research Program (to W.J.P. and S.L.), and an NSF Graduate Research Fellowship (to D.U.G.).

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.

UR - https://www.scopus.com/pages/publications/84889578835

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 -

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

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