2026-06-14T03:31:21Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/54082024-09-27T08:33:39Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
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
funder
Ministerio de Economía, Industria y Competitividad (España)
funder
Comunidad de Madrid (España)
funder
Regional Government of Andalusia (España)
funder
Fundación ProCNIC
2017-11-27T13:49:52Z
2017-11-27T13:49:52Z
2015
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
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.
eng
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
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