A Functional Variant Associated with Atrial Fibrillation Regulates PITX2c Expression through TFAP2a

The most significantly associated genetic locus for atrial fibrillation (AF) is in chromosomal region 4q25, where four independent association signals have been identified. Although model-system studies suggest that altered PITX2c expression might underlie the association, the link between specific...

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Vydané v:American journal of human genetics Ročník 99; číslo 6; s. 1281
Hlavní autori: Ye, Jiangchuan, Tucker, Nathan R, Weng, Lu-Chen, Clauss, Sebastian, Lubitz, Steven A, Ellinor, Patrick T
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 01.12.2016
Predmet:
Alleles
Animals
Atrial Fibrillation - genetics
Chromosomes, Human, Pair 4 - genetics
Conserved Sequence - genetics
Deoxyribonucleases - metabolism
Enhancer Elements, Genetic - genetics
Gene Expression Regulation
Genetic Predisposition to Disease
Histones - chemistry
Histones - metabolism
Homeobox Protein PITX2
Homeodomain Proteins - genetics
Humans
Mammals - genetics
Myocytes, Cardiac - cytology
Polymorphism, Single Nucleotide - genetics
Transcription Factor AP-2 - metabolism
Transcription Factors - genetics
Zebrafish - genetics
ISSN:1537-6605, 1537-6605
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Popis
Shrnutí:The most significantly associated genetic locus for atrial fibrillation (AF) is in chromosomal region 4q25, where four independent association signals have been identified. Although model-system studies suggest that altered PITX2c expression might underlie the association, the link between specific variants and the direction of effect on gene expression remains unknown for all four signals. In the present study, we analyzed the AF-associated region most proximal to PITX2 at 4q25. First, we identified candidate regulatory variants that might confer AF risk through a combination of mammalian conservation, DNase hypersensitivity, and histone modification from ENCODE and the Roadmap Epigenomics Project, as well as through in vivo analysis of enhancer activity in embryonic zebrafish. Within candidate regions, we then identified a single associated SNP, rs2595104, which displayed dramatically reduced enhancer activity with the AF risk allele. CRISPR-Cas9-mediated deletion of the rs2595104 region and editing of the rs2595104 risk allele in human stem-cell-derived cardiomyocytes resulted in diminished PITX2c expression in comparison to that of the non-risk allele. This differential activity was mediated by activating enhancer binding protein 2 alpha (TFAP2a), which bound robustly to the non-risk allele at rs2595104, but not to the risk allele, in cardiomyocytes. In sum, we found that the AF-associated SNP rs2595104 altered PITX2c expression via interaction with TFAP2a. Such a pathway could ultimately contribute to AF susceptibility at the PITX2 locus associated with AF.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1537-6605
1537-6605
DOI:10.1016/j.ajhg.2016.10.001