{Reference Type}: Journal Article
{Title}: Long-range Pitx2c enhancer-promoter interactions prevent predisposition to atrial fibrillation.
{Author}: Zhang M;Hill MC;Kadow ZA;Suh JH;Tucker NR;Hall AW;Tran TT;Swinton PS;Leach JP;Margulies KB;Ellinor PT;Li N;Martin JF;
{Journal}: Proc Natl Acad Sci U S A
{Volume}: 116
{Issue}: 45
{Year}: 11 2019 5
{Factor}: 12.779
{DOI}: 10.1073/pnas.1907418116
{Abstract}: Genome-wide association studies found that increased risk for atrial fibrillation (AF), the most common human heart arrhythmia, is associated with noncoding sequence variants located in proximity to PITX2 Cardiomyocyte-specific epigenomic and comparative genomics uncovered 2 AF-associated enhancers neighboring PITX2 with varying conservation in mice. Chromosome conformation capture experiments in mice revealed that the Pitx2c promoter directly contacted the AF-associated enhancer regions. CRISPR/Cas9-mediated deletion of a 20-kb topologically engaged enhancer led to reduced Pitx2c transcription and AF predisposition. Allele-specific chromatin immunoprecipitation sequencing on hybrid heterozygous enhancer knockout mice revealed that long-range interaction of an AF-associated region with the Pitx2c promoter was required for maintenance of the Pitx2c promoter chromatin state. Long-range looping was mediated by CCCTC-binding factor (CTCF), since genetic disruption of the intronic CTCF-binding site caused reduced Pitx2c expression, AF predisposition, and diminished active chromatin marks on Pitx2 AF risk variants located at 4q25 reside in genomic regions possessing long-range transcriptional regulatory functions directed at PITX2.