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| Status |
Public on Jul 16, 2020 |
| Title |
Super-Enhancer-Associated Aortic Valve Stenosis Risk Locus 1p21.2 Alters NFATC2 Binding Site and Promotes Fibrogenesis [H3K27ac HiChIP] |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
Genome-wide association studies identified a strong signal for non coding variants at the 1p21.2 locus associated with calcific aortic valve stenosis (CAVS). Regulation at the locus and impact on the biology of the aortic valve is presently unknown. Integrative mapping of genetic association data was performed. The locus was evaluated by 3D genome mapping, analysis of atomic resolution data, DNA-binding assay and CRISPR activation (CRISPRa). Weighted gene co-expression network analysis (WGCNA) was performed to determine regulatory network in CAVS. The functional impact of the locus was assessed in isolated VICs. Fine-grained mapping at 1p21.2 risk locus identified rs6702619 as being located in open chromatin and a distant-acting super-enhancer including chromatin interaction with the promoter of PALMD in VICs. Atomic-level data showed that the risk variant modified base readout and DNA shape, which prevented the recruitment of NFATC2, a transcription factor involved in heart valve morphogenesis, and lowered the expression of PALMD. CRISPRa confirmed that rs6702619 exerts a control on the expression of PALMD. WGCNA performed in 233 calcified aortic valves identified a co-expression network encompassing PALMD, which was enriched in actin-based process. In LC-MS/MS and co-immunoprecipitation assay, actin was identified as a protein interacting with PALMD. Lower expression of PALMD in VICs promoted the polymerization of actin, the activation of myocardin-related transcription factor and fibrogenesis. Risk allele at rs6702619 disrupts a NFATC2 binding site and decreases enhancer-mediated expression of PALMD, which results in actin polymerization, a myofibroblast-like phenotype in VICs and fibrogenesis, a key underpinning process in the pathogenesis of CAVS.
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| Overall design |
H3K27ac HiChIP in human aortic valve interstitial cells.
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| Contributor(s) |
Chignon A, Rosa M, Boulanger M, Argaud D, Devillers R, Bon-Baret V, Mkannez G, Li Z, Gaudreault N, Gosselin D, Thériault S, Bossé Y, Mathieu P |
| Citation(s) |
35041643 |
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| Submission date |
Jul 15, 2020 |
| Last update date |
Feb 02, 2022 |
| Contact name |
Patrick Mathieu |
| E-mail(s) |
patrick.mathieu@fmed.ulaval.ca
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| Organization name |
Quebec Heart and Lung Institute
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| Street address |
2725 Ch Ste-Foy
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| City |
Québec |
| State/province |
QC |
| ZIP/Postal code |
G1V 4G5 |
| Country |
Canada |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (1) |
| GSM4672364 |
H3K27ac HiChIP in human aortic valve interstitial cells |
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| This SubSeries is part of SuperSeries: |
| GSE154513 |
Super-Enhancer-Associated Aortic Valve Stenosis Risk Locus 1p21.2 Alters NFATC2 Binding Site and Promotes Fibrogenesis |
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| Relations |
| BioProject |
PRJNA646510 |
| SRA |
SRP272124 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE154512_RAW.tar |
891.2 Mb |
(http)(custom) |
TAR (of BW, HIC) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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