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Series GSE201570 Query DataSets for GSE201570
Status Public on Oct 31, 2022
Title FHL5 cofactor mediates vascular disease risk by regulating smooth muscle cell transcriptional networks [CUT&RUN]
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Genome-wide association studies (GWAS) have identified hundreds of loci associated with vascular diseases such as coronary artery disease (CAD) and myocardial infarction (MI), and hypertension. However, the biological roles for many of these loci enriched in the vessel wall remains unknown. Among these, UFL1-FHL5 (chr6q16.1) emerged as a genome-wide significant locus in a recent CAD/MI meta-analysis. Here, we use an integrative approach leveraging human genetics, epigenomic profiling, and in vitro functional and ex vivo imaging analyses to prioritize FHL5 as the top candidate causal gene and reveal the molecular mechanisms of its pleiotropic genetic associations. Notably, FHL5 overexpression in coronary artery smooth muscle cells (SMC) increased vascular calcification and dysregulated processes related to extracellular matrix organization and calcium handling. Lastly, by mapping FHL5 binding sites genome-wide using CUT&RUN, we identified regulatory interactions with downstream disease loci having putative roles in SMC phenotypic modulation. Together, these trans-acting mechanisms may account for a portion of the heritable risk for CAD/MI and other complex vascular diseases.
Overall design To identify FHL5 genome-wide binding sites, CUT&RUN experiments were performed using FHL5, CREB, H3K4me3, and H3K27ac antibodies using 250,000 HCASMC-hTERTs grown under basal conditions as input. The IgG and HCASMC-hTERT (with no FHL5 expression) samples were included as controls. We conducted at least 2 technical replicates per cell line for each antibody.  Next generation sequencing was performed on an Illumina NextSeq 2000 or Illumina NextSeq 500 instrument.
Contributor(s) Wong D, Miller CL
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Submission date Apr 26, 2022
Last update date Nov 02, 2022
Contact name Clint L Miller
Organization name University of Virginia
Department Center for Public Health Genomics
Street address PO Box 800717
City Charlottesville
State/province VA
ZIP/Postal code 22908
Country USA
Platforms (2)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
GPL30173 NextSeq 2000 (Homo sapiens)
Samples (8)
GSM6067637 HCASMC-hTERT-FHL5_IgG_rep1
GSM6067638 HCASMC-hTERT-FHL5_H3K4me3_rep1
GSM6067639 HCASMC-hTERT-HA_FHL5_rep1
This SubSeries is part of SuperSeries:
GSE201572 FHL5 cofactor mediates vascular disease risk by regulating smooth muscle cell transcriptional networks
BioProject PRJNA832252

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE201570_FHL5_pooled_peaks.narrowPeak.bed.gz 367.7 Kb (ftp)(http) BED
GSE201570_IgG_pooled_peaks.narrowPeak.gz 69.2 Kb (ftp)(http) NARROWPEAK
GSE201570_RAW.tar 3.4 Mb (http)(custom) TAR (of NARROWPEAK)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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