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| Status |
Public on Oct 08, 2019 |
| Title |
Long-range Pitx2c Enhancer Promoter Interactions Prevent Predisposition to Atrial Fibrillation [RNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Genome-wide association studies (GWAS) have found that increased risk for atrial fibrillation (AF), the most common type of arrhythmia in humans, is associated with non-coding sequence variants located in proximity to the PITX2 homeobox gene. Using cardiomyocyte-specific epigenomic and comparative genomic analyses, we identified two AF-associated enhancers neighboring PITX2 with varying degrees of conservation in mice. Pitx2c promoter directly contacted the AF-associated enhancer regions. CRISPR/Cas9 mediated deletion of a 20 kb long topologically engaged enhancer lead to reduced Pitx2c transcription and AF predisposition. Allele-specific ChIP-seq and CUT&RUN experiments showed that long-range interaction of this AF-associated region with the Pitx2c promoter was required for maintenance of the Pitx2c promoter chromatin state. Moreover, long-range looping was mediated by CTCF, as the genetic disruption of an intronic CTCF binding site caused decreased Pitx2c cardiac expression, AF predisposition, and reduced active chromatin marks on Pitx2. Our findings reveal that AF risk variants located at 4q25 reside in genomic regions possessing long-range transcriptional regulatory functions directed at PITX2
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| Overall design |
Epigenetic and transcriptomic analyses were performed on left ventricular tissue of FVB control and Pitx2 Enh20k Deletion mice.
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| |
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| Contributor(s) |
Zhang M, Hill MC, Kadow ZA, Martin JF |
| Citation(s) |
31636200 |
| |
| Submission date |
Oct 07, 2019 |
| Last update date |
Jan 07, 2020 |
| Contact name |
Min Zhang |
| E-mail(s) |
minzhang5099@gmail.com
|
| Organization name |
Baylor College of Medicine
|
| Department |
Department of Molecular Physiology
|
| Lab |
James F Martin
|
| Street address |
One Baylor Plaza Room 504E
|
| City |
Houston |
| State/province |
Texas |
| ZIP/Postal code |
77030 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
|
| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE138530 |
Long-range Pitx2c Enhancer Promoter Interactions Prevent Predisposition to Atrial Fibrillation |
|
| Relations |
| BioProject |
PRJNA576255 |
| SRA |
SRP224655 |
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