Molecular mechanisms of coronary disease revealed using quantitative trait loci for TCF21 binding, chromatin accessibility, and chromosomal looping.

Genome Biology
Quanyi ZhaoThomas Quertermous

Abstract

To investigate the epigenetic and transcriptional mechanisms of coronary artery disease (CAD) risk, as well as the functional regulation of chromatin structure and function, we create a catalog of genetic variants associated with three stages of transcriptional cis-regulation in primary human coronary artery vascular smooth muscle cells (HCASMCs). We use a pooling approach with HCASMC lines to map regulatory variants that mediate binding of the CAD-associated transcription factor TCF21 with ChIPseq studies (bQTLs), variants that regulate chromatin accessibility with ATACseq studies (caQTLs), and chromosomal looping with Hi-C methods (clQTLs). We examine the overlap of these QTLs and their relationship to smooth muscle-specific genes and transcription factors. Further, we use multiple analyses to show that these QTLs are highly associated with CAD GWAS loci and correlate to lead SNPs where they show allelic effects. By utilizing genome editing, we verify that identified functional variants can regulate both chromatin accessibility and chromosomal looping, providing new insights into functional mechanisms regulating chromatin state and chromosomal structure. Finally, we directly link the disease-associated TGFB1-SMAD3 pathway to ...Continue Reading

Associated Datasets

References

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Citations

Jan 8, 2021·Annals of the Rheumatic Diseases·Akari SuzukiKazuhiko Yamamoto
Apr 30, 2021·Circulation Research·Mark C BlaserElena Aikawa
Jul 9, 2021·Frontiers in Endocrinology·Vinay Singh TanwarRama Natarajan
Feb 1, 2022·PLoS Genetics·Elise D FlynnTuuli Lappalainen
Jan 7, 2022·Circulation·Paul ChengThomas Quertermous

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Methods Mentioned

BETA
genotyping
ChIPseq
Hi-C
ATACseq
ChIP
PCR
transfection

Software Mentioned

MEME
hicpro2juicebox
bed2GwasCatalogBinomialMod1Ggplot
Hi
bigWig
HOMER findMotifs . pl
hicFindTADs
bedtools
hicCorrectMatrix
samtools

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