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oai:repisalud.isciii.es:20.500.12105/54082024-09-27T08:33:39Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Aguirre, Luis A. author Alonso, M. Eva author Badia-Careaga, Claudio author Rollan, Isabel author Arias, Cristina author Fernandez-Minan, Ana author Lopez-Jimenez, Elena author Aranega, Amelia author Gomez-Skarmeta, Jose Luis author Franco, Diego author Manzanares, Miguel author 2015 Background: 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. Results: 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. Conclusions: 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. BMC Biol. 2015; 13(1):26 10.1186/s12915-015-0138-0 1741-7007 BMC Biology 25888893 http://hdl.handle.net/20.500.12105/5408 Atrial fibrillation Chromosome conformation ENPEP PITX2 Regulatory element GENOME-WIDE ASSOCIATION LEFT-RIGHT ASYMMETRY TRANSPOSABLE ELEMENTS AMINOPEPTIDASE-A CHROMOSOME 4Q25 COMMON VARIANTS GENE-EXPRESSION HUMAN ENHANCERS DNA ELEMENTS HEART Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP