2024-03-28T08:49:20Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1296242021-12-27T15:52:02Zcom_10261_128com_10261_1col_10261_381
Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP
Alonso, M. Eva
Fernández-Miñán, Ana
Gómez-Skarmeta, José Luis
Manzanares, Miguel
Junta de Andalucía
Comunidad de Madrid
Ministerio de Economía y Competitividad (España)
Centro Nacional de Investigaciones Cardiovasculares (España)
Fundación Pro CNIC
Atrial fibrillation
Regulatory element
PITX2
Chromosome conformation
ENPEP
This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al.
[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.
2016-03-01T13:09:42Z
2016-03-01T13:09:42Z
2015
2016-03-01T13:09:42Z
artículo
BMC Biology 13: 26 (2015)
http://hdl.handle.net/10261/129624
10.1186/s12915-015-0138-0
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100005884
http://dx.doi.org/10.13039/100012818
http://dx.doi.org/10.13039/501100011011
25888893
eng
Publisher's version
http://dx.doi.org/10.1186/s12915-015-0138-0
Sí
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2013-41322-P
S2010/BMD-2315/CELLDD
http://creativecommons.org/licenses/by/4.0
openAccess
BioMed Central