3 research outputs found
Long-range regulatory interactions at the 4q25 atrial fibrillation risk locus involve PITX2c and ENPEP
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.We thank Miguel Torres and members of the Manzanares lab for support and
comments; Christine Mummery, Jose Luis de la Pompa and Joaquin
Rodriguez-Leon for reagents; the CNIC Transgenic Unit for generation of
embryos; Stuart Pocock for statistical advice; and Simon Bartlett for
English editing. This study was funded by the CNIC Translational Grant
Programme (CNIC-08-2009 to MM and DF), the Spanish Ministerio de
Economia y Competitividad (grants BFU2011-23083 to MM, BFU2013-41322-P
to JLGS, BFU2012-38111 to AA, and CSD2007-00008 to JLGS and MM), the
Comunidad Autonoma de Madrid (grant CELLDD-CM to MM), and the Andalusian
Government (grant BIO-396 to JLGS). The CNIC is supported by the Spanish
Ministerio de Economia y Competitividad and the Pro-CNIC Foundation.S
Potentiation effect of the AMPK activator A-769662 on cardiac myocytes metabolism and survival
Abstract 286 van Poster session 2 Frontiers in CardioVascular Biology, London 30th March – 1st April 2012 Second Congress of the ESC Council on Basic Cardiovascular Science