Long-range Pitx2c enhancer-promoter interactions prevent predisposition to atrial fibrillation.

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.

authors

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

doi

10.1073/pnas.1907418116

subject

Has Abstract

pub_date

2019-11-05 00:00:00

pages

22692-22698

issue

45

eissn

0027-8424

issn

1091-6490

pii

1907418116

journal_volume

116

pub_type

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