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 |
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| Hlavní autori: | , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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01.12.2016
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| Abstract | 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. |
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| AbstractList | 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.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. 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. |
| Author | Tucker, Nathan R Lubitz, Steven A Ellinor, Patrick T Ye, Jiangchuan Clauss, Sebastian Weng, Lu-Chen |
| Author_xml | – sequence: 1 givenname: Jiangchuan surname: Ye fullname: Ye, Jiangchuan organization: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA – sequence: 2 givenname: Nathan R surname: Tucker fullname: Tucker, Nathan R organization: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA – sequence: 3 givenname: Lu-Chen surname: Weng fullname: Weng, Lu-Chen organization: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA – sequence: 4 givenname: Sebastian surname: Clauss fullname: Clauss, Sebastian organization: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA – sequence: 5 givenname: Steven A surname: Lubitz fullname: Lubitz, Steven A organization: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA – sequence: 6 givenname: Patrick T surname: Ellinor fullname: Ellinor, Patrick T email: ellinor@mgh.harvard.edu organization: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: ellinor@mgh.harvard.edu |
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| SubjectTerms | 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 |
| Title | A Functional Variant Associated with Atrial Fibrillation Regulates PITX2c Expression through TFAP2a |
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