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SRX8740249: GSM4672357: ATAC-seq in human aortic valve interstitial cells; Homo sapiens; ATAC-seq
1 ILLUMINA (Illumina HiSeq 4000) run: 56.5M spots, 4.3G bases, 1.5Gb downloads

Submitted by: NCBI (GEO)
Study: Super-Enhancer-Associated Aortic Valve Stenosis Risk Locus 1p21.2 Alters NFATC2 Binding Site and Promotes Fibrogenesis [ATAC-Seq]
show Abstracthide Abstract
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. Overall design: ATAC-seq in human aortic valve interstitial cells.
Sample: ATAC-seq in human aortic valve interstitial cells
SAMN15545075 • SRS7012776 • All experiments • All runs
Organism: Homo sapiens
Library:
Instrument: Illumina HiSeq 4000
Strategy: ATAC-seq
Source: GENOMIC
Selection: other
Layout: SINGLE
Construction protocol: Human aortic valve interstitial cells were isolated from control non-mineralized aortic valves obtained from patients undergoing heart transplantation. The protocol was approved by the local ethical committee and informed consent was obtained from the subjects. Aortic leaflets were cut into pieces and incubated in 0.3% type I collagenase (Invitrogen, Thermo Fisher Scientific, ON, Canada) at 37°C for 45 minutes, then filtered through a 70 µm mesh, centrifuged for 5 minutes at 1,500 rpm and resuspended in complete media (DMEM, 10% FBS with L-glutamine and sodium pyruvate). Cells were used between passages 3 to 7. Nuclei from approximatively 2.5-4 x 105 cells were prepared as previously described (Shashikant T, et al. 2018, BMC Genomics). Libraries were first amplified for 5 cycles using custom-synthesized index primers and then a second amplification was performed. The appropriate number of additional PCR cycles was determined using quantitative real-time PCR by plotting the Rn value (fluorescent signal from SYBR Green I) versus cycle number and determining the cycle number corresponding to one-third of the maximum fluorescent intensity. Libraries were PCR-amplified for 4-7 cycles. After PCR amplification, libraries were purified using DNA clean up & concentrator kit (Zymo Research, Cedarlane, Canada)Library quality was assessed on a BioAnalyser (Agilent, ON, Canada) using Agilent High Sensitivity DNA kit (Agilent, ON, Canada). Sequencing was performed on an Illumina HiSeq4000 (UCSD IGM Genomics Facility, CA, USA).
Experiment attributes:
GEO Accession: GSM4672357
Links:
Runs: 1 run, 56.5M spots, 4.3G bases, 1.5Gb
Run# of Spots# of BasesSizePublished
SRR1223175056,520,3554.3G1.5Gb2020-07-16

ID:
11367833

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