PMID:22234890

Citation	Visser, M, Kayser, M and Palstra, RJ (2012) HERC2 rs12913832 modulates human pigmentation by attenuating chromatin-loop formation between a long-range enhancer and the OCA2 promoter. Genome Res. 22:446-55
Abstract	Pigmentation of skin, eye, and hair reflects some of the most evident common phenotypes in humans. Several candidate genes for human pigmentation are identified. The SNP rs12913832 has strong statistical association with human pigmentation. It is located within an intron of the nonpigment gene HERC2, 21 kb upstream of the pigment gene OCA2, and the region surrounding rs12913832 is highly conserved among animal species. However, the exact functional role of HERC2 rs12913832 in human pigmentation is unknown. Here we demonstrate that the HERC2 rs12913832 region functions as an enhancer regulating OCA2 transcription. In darkly pigmented human melanocytes carrying the rs12913832 T-allele, we detected binding of the transcription factors HLTF, LEF1, and MITF to the HERC2 rs12913832 enhancer, and a long-range chromatin loop between this enhancer and the OCA2 promoter that leads to elevated OCA2 expression. In contrast, in lightly pigmented melanocytes carrying the rs12913832 C-allele, chromatin-loop formation, transcription factor recruitment, and OCA2 expression are all reduced. Hence, we demonstrate that allelic variation of a common noncoding SNP located in a distal regulatory element not only disrupts the regulatory potential of this element but also affects its interaction with the relevant promoter. We provide the key mechanistic insight that allele-dependent differences in chromatin-loop formation (i.e., structural differences in the folding of gene loci) result in differences in allelic gene expression that affects common phenotypic traits. This concept is highly relevant for future studies aiming to unveil the functional basis of genetically determined phenotypes, including diseases.
Links	PubMed PMC3290780 Online version:10.1101/gr.128652.111
Keywords	Alleles; Cell Line; Chromatin/chemistry; Enhancer Elements, Genetic; Gene Expression Regulation; Guanine Nucleotide Exchange Factors/genetics; Guanine Nucleotide Exchange Factors/metabolism; Humans; Melanocytes/metabolism; Membrane Transport Proteins/genetics; Organ Specificity/genetics; Pigmentation/genetics; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:MITF	involved_in	GO:0010628: positive regulation of gene expression	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:MITF	involved_in	GO:0010628: positive regulation of gene expression	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:MITF		GO:0010628: positive regulation of gene expression	ECO:0000314:		P		The over-expression of the transcription factor MITF in HEMn-LP cells (cells with the C-allele, which have lighter pigmentation)led to increased OCA2 expression, which darkened the pigmentation of the cell (Figure 4-E).	complete CACAO 9954
HUMAN:MITF		GO:0010628: positive regulation of gene expression	ECO:0000315:		P		The over-expression of the negative transcription form of MITF in HEMn-LP cells (dnMITF )led to decreased OCA2 expression, which lightened the pigmentation of the cell (Figure 4E). This was an IMP was the conclusion about the role of MITF was drawn from a mutant phenotype.	complete CACAO 9956
HUMAN:A8KAQ8		GO:0010628: positive regulation of gene expression	ECO:0000314:		P		The over-expression of transcription factor HLTF led to an elevated expression of OCA2, which leads to a darker pigmentation (Figure 4B), when bound to the HERC2 region. This is an IDA because the levels of HLTF correlated to a darker pigmentation when bound to HERC2. Therefore, HERC2 positively regulates the expression of the gene for dark pigment.	complete CACAO 9949
HUMAN:A8KAQ8		GO:0046158: ocellus pigment metabolic process	ECO:0000314:		P		The over-expression of the transcription factor MITF in HEMn-LP cells (cells with the C-allele, which have lighter pigmentation)led to increased OCA2 expression, which darkened the pigmentation of the eye (Figure 4-E).	complete CACAO 9952

References

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