Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP.
Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP.
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DOI：
10.1186/s12915-015-0138-0
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发表时间：
2015-04-17
期刊：
影响因子：
5.4
通讯作者：
Manzanares M
中科院分区：
文献类型：
--
作者：
Aguirre LA;Alonso ME;Badía-Careaga C;Rollán I;Arias C;Fernández-Miñán A;López-Jiménez E;Aránega A;Gómez-Skarmeta JL;Franco D;Manzanares M
最近的全基因组关联研究发现了导致心房颤动（人类主要心律失常）风险增加的基因组位点。最重要的基因座位于4 q25的基因沙漠中，PITX 2上游约170个酶，其编码参与胚胎左右不对称和心脏发育的转录因子。然而，该基因组区域在功能和结构上如何与PITX 2和房颤相关尚不清楚。为了验证其功能，我们在小鼠心房心肌细胞系和转基因小鼠胚胎中测试了4 q25基因组片段的转录活性，确定了一个非组织特异性增效剂调节元件。染色体构象捕获显示，该区域与心脏特异性Pitx 2亚型的启动子相互作用。令人惊讶的是，这个调节区还与下一个邻近基因Enpep的启动子相互作用，我们发现该基因在发育中的小鼠心脏对心电活动至关重要的区域中表达。我们的数据表明，PITX 2和ENPEP的失调可能导致疾病相关变异携带者房颤风险增加，并显示了我们在全基因组疾病关联的功能分析中面临的挑战。本文的在线版本（doi：10.1186/s12915-015-0138-0）包含补充材料，可供授权用户使用。
Recent genome-wide association studies have uncovered genomic loci that underlie an increased risk for atrial fibrillation, the major cardiac arrhythmia in humans. The most significant locus is located in a gene desert at 4q25, approximately 170 kilobases upstream of PITX2, which codes for a transcription factor involved in embryonic left-right asymmetry and cardiac development. However, how this genomic region functionally and structurally relates to PITX2 and atrial fibrillation is unknown. To characterise its function, we tested genomic fragments from 4q25 for transcriptional activity in a mouse atrial cardiomyocyte cell line and in transgenic mouse embryos, identifying a non-tissue-specific potentiator regulatory element. Chromosome conformation capture revealed that this region physically interacts with the promoter of the cardiac specific isoform of Pitx2. Surprisingly, this regulatory region also interacts with the promoter of the next neighbouring gene, Enpep, which we show to be expressed in regions of the developing mouse heart essential for cardiac electrical activity. Our data suggest that de-regulation of both PITX2 and ENPEP could contribute to an increased risk of atrial fibrillation in carriers of disease-associated variants, and show the challenges that we face in the functional analysis of genome-wide disease associations. The online version of this article (doi:10.1186/s12915-015-0138-0) contains supplementary material, which is available to authorized users.
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