title: A single nucleotide polymorphism associated with isolated cleft lip and palate, thyroid cancer and hypothyroidism alters the activity of an oral epithelium and thyroid enhancer near FOXE1.
abstract: Three common diseases, isolated cleft lip and cleft palate (CLP), hypothyroidism and thyroid cancer all map to the FOXE1 locus, but causative variants have yet to be identified. In patients with CLP, the frequency of coding mutations in FOXE1 fails to account for the risk attributable to this locus, suggesting that the common risk alleles reside in nearby regulatory elements. Using a combination of zebrafish and mouse transgenesis, we screened 15 conserved non-coding sequences for enhancer activity, identifying three that regulate expression in a tissue specific pattern consistent with endogenous foxe1 expression. These three, located -82.4, -67.7 and +22.6 kb from the FOXE1 start codon, are all active in the oral epithelium or branchial arches. The -67.7 and +22.6 kb elements are also active in the developing heart, and the -67.7 kb element uniquely directs expression in the developing thyroid. Within the -67.7 kb element is the SNP rs7850258 that is associated with all three diseases. Quantitative reporter assays in oral epithelial and thyroid cell lines show that the rs7850258 allele (G) associated with CLP and hypothyroidism has significantly greater enhancer activity than the allele associated with thyroid cancer (A). Moreover, consistent with predicted transcription factor binding differences, the -67.7 kb element containing rs7850258 allele G is significantly more responsive to both MYC and ARNT than allele A. By demonstrating that this common non-coding variant alters FOXE1 expression, we have identified at least in part the functional basis for the genetic risk of these seemingly disparate disorders.
authors: Department of Orthodontics, andrew-lidral@uiowa.edu.
authors: Andrew C
authors: AC
authors: Lidral
authors: Dows Research Institute, State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
authors: Huan
authors: H
authors: Liu
authors: Department of Endocrinology and.
authors: Steven A
authors: SA
authors: Bullard
authors: Department of Anatomy, University of Iowa, Iowa City, IA, USA.
authors: Greg
authors: G
authors: Bonde
authors: Department of Oral and Maxillofacial Surgery, Toyota Memorial Hospital, Toyota City, Aichi, Japan.
authors: Junichiro
authors: J
authors: Machida
authors: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA and Department of Energy Joint Genome Institute, Walnut Creek, CA, USA.
authors: Axel
authors: A
authors: Visel
authors: Department of Orthodontics.
authors: Lina M Moreno
authors: LM
authors: Uribe
authors: Department of Anatomy, University of Iowa, Iowa City, IA, USA.
authors: Xiao
authors: X
authors: Li
authors: Department of Anatomy, University of Iowa, Iowa City, IA, USA.
authors: Brad
authors: B
authors: Amendt
authors: Department of Anatomy, University of Iowa, Iowa City, IA, USA.
authors: Robert A
authors: RA
authors: Cornell
mesh_terms: D000483:Alleles; D000818:Animals; D002460:Cell Line; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D003001:Cloning, Molecular; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010159:Palate / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; C472789:Foxe1 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
references: Eur J Endocrinol. 2011 May;164(5):781-8
references: 21367965
references: Mod Pathol. 2008 Feb;21(2):192-200
references: 18084247
references: Br J Dermatol. 2010 May;162(5):1093-7
references: 19845668
references: PLoS One. 2012;7(4):e34442
references: 22493691
references: Dev Cell. 2009 Dec;17(6):836-48
references: 20059953
references: Genesis. 2007 Jun;45(6):382-90
references: 17523175
references: Thyroid. 2014 Apr;24(4):649-54
references: 24219130
references: Am J Med Genet A. 2004 Sep 15;130A(1):40-4
references: 15368494
references: Clin Endocrinol (Oxf). 2012 Dec;77(6):926-33
references: 22882326
references: J Clin Endocrinol Metab. 2015 Jan;100(1):E164-72
references: 25303483
references: Mech Dev. 1998 Apr;73(1):117-23
references: 9545558
references: Hum Mol Genet. 2010 Jun 15;19(12):2516-23
references: 20350937
references: EMBO J. 1997 Jun 2;16(11):3185-97
references: 9214635
references: PLoS Genet. 2009 Sep;5(9):e1000637
references: 19730683
references: Nucleic Acids Res. 2014 Jan;42(Database issue):D142-7
references: 24194598
references: J Pediatr. 2009 Dec;155(6):909-13
references: 19656524
references: N Engl J Med. 2010 Jul 8;363(2):166-76
references: 20647212
references: Int J Cancer. 2014 Apr 1;134(7):1659-68
references: 24105688
references: Teratog Carcinog Mutagen. 1984;4(5):427-36
references: 6150558
references: Hum Mol Genet. 2002 Aug 15;11(17):2051-9
references: 12165566
references: Cancer. 2011 Jul 1;117(13):2898-909
references: 21692051
references: PLoS One. 2012;7(12):e51954
references: 23251661
references: J Exp Zool B Mol Dev Evol. 2009 Dec 15;312(8):827-40
references: 19488987
references: Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000 Sep;90(3):340-7
references: 10982956
references: Int Arch Occup Environ Health. 2006 May;79(5):396-404
references: 16217675
references: Nature. 2006 Nov 23;444(7118):499-502
references: 17086198
references: Inflamm Bowel Dis. 2014 Feb;20(2):271-7
references: 24280874
references: Hum Mol Genet. 2014 Oct 15;23(20):5505-17
references: 24852370
references: Am J Med Genet C Semin Med Genet. 2013 Nov;163C(4):246-58
references: 24124047
references: Birth Defects Res A Clin Mol Teratol. 2011 Apr;91(4):218-25
references: 21462296
references: Genome Res. 2005 Aug;15(8):1034-50
references: 16024819
references: Int J Cancer. 2014 May 1;134(9):2098-107
references: 24127282
references: Nat Genet. 2010 Jan;42(1):24-6
references: 20023658
references: J Clin Endocrinol Metab. 1999 Jul;84(7):2502-6
references: 10404827
references: Hum Mol Genet. 2009 Dec 15;18(24):4879-96
references: 19779022
references: Am J Med Genet. 1997 Oct 3;72(1):120-1
references: 9295089
references: PLoS Biol. 2011 Jan 18;9(1):e1000582
references: 21267068
references: PLoS One. 2011;6(9):e24824
references: 21935474
references: Nat Genet. 1998 Aug;19(4):395-8
references: 9697704
references: Cancer Res. 2003 Jul 1;63(13):3735-42
references: 12839967
references: Am J Hum Genet. 2014 Jun 5;94(6):854-69
references: 24857694
references: Dev Dyn. 1995 Oct;204(2):144-55
references: 8589438
references: J Clin Endocrinol Metab. 2006 Oct;91(10):4183-7
references: 16882747
references: Development. 2012 Feb;139(4):720-30
references: 22241841
references: Cancer Biomark. 2010-2011;8(1):43-51
references: 21896990
references: Science. 2006 Apr 14;312(5771):276-9
references: 16556802
references: J Clin Endocrinol Metab. 2013 Oct;98(10):E1674-81
references: 23894154
references: Horm Res Paediatr. 2011;75(5):329-34
references: 21311165
references: Nat Protoc. 2007;2(4):924-32
references: 17446874
references: BMC Dev Biol. 2007 Jun 27;7:75
references: 17597528
references: PLoS Genet. 2009 Feb;5(2):e1000365
references: 19197348
references: Nat Genet. 2012 Sep;44(9):968-71
references: 22863734
references: Proc Natl Acad Sci U S A. 1980 Jun;77(6):3455-9
references: 6106191
references: Am J Epidemiol. 1999 Jan 1;149(1):64-74
references: 9883795
references: PLoS Genet. 2013;9(2):e1003266
references: 23408906
references: Nat Genet. 2009 Apr;41(4):460-4
references: 19198613
references: J Clin Endocrinol Metab. 2012 Sep;97(9):E1814-9
references: 22736773
references: Nat Genet. 2007 May;39(5):596-604
references: 17435756
references: Mol Endocrinol. 1992 Aug;6(8):1310-7
references: 1406708
references: Nat Protoc. 2006;1(3):1297-305
references: 17406414
references: Methods Mol Biol. 2009;561:41-63
references: 19504063
references: J Clin Endocrinol Metab. 2002 Feb;87(2):557-62
references: 11836285
references: Nat Genet. 1998 Aug;19(4):399-401
references: 9697705
references: J Med Genet. 2011 Sep;48(9):645-8
references: 21730105
references: Science. 2013 Oct 25;342(6157):1241006
references: 24159046
references: J Histochem Cytochem. 2003 Jan;51(1):41-54
references: 12502753
references: Nature. 2005 Aug 11;436(7052):807-11
references: 16094360
references: Neoplasia. 2014 Sep;16(9):757-69
references: 25246276
references: Eur J Endocrinol. 2001 Oct;145(4):385-9
references: 11580993
references: Cleft Palate Craniofac J. 1997 May;34(3):206-10
references: 9167070
references: Nat Genet. 2010 Jun;42(6):525-9
references: 20436469
references: Genome Res. 2002 Apr;12(4):656-64
references: 11932250
references: Hum Genet. 2007 Dec;122(5):467-76
references: 17717707
references: Genome Res. 2008 Feb;18(2):252-60
references: 18071029
references: J Cell Mol Med. 2012 Oct;16(10):2362-8
references: 22304410
references: BMC Genomics. 2009 Jan 07;10:8
references: 19128492
references: J Invest Dermatol. 2004 May;122(5):1180-7
references: 15140221
references: J Dent Res. 2014 Apr;93(4):376-81
references: 24563486
references: Am J Hum Genet. 2011 Oct 7;89(4):529-42
references: 21981779
references: Pediatr Res. 2013 Apr;73(4 Pt 1):484-91
references: 23344678
references: Br J Cancer. 1996 Jul;74(2):246-50
references: 8688329
references: Int J Dev Biol. 2013;57(1):55-60
references: 23585353
references: Nucleic Acids Res. 2008 Aug;36(14):4689-98
references: 18628296
references: Laryngoscope. 2012 Sep;122(9):2082-7
references: 22753311
references: Nat Rev Genet. 2011 Mar;12(3):167-78
references: 21331089
references: Am J Hum Genet. 2004 Apr;74(4):761-4
references: 15024693
references: Endocr Relat Cancer. 2005 Jun;12(2):319-34
references: 15947106