Molecular mechanisms of coronary artery disease GWAS gene TCF21 – genomic association with serum response factor SRF on open-close chromatin alternation

Coronary artery disease (CAD) GWAS gene, TCF21 has been shown to act as a causal gene for the disease development. Here, I present various molecular associations on the genomic level that suggest potential mechanisms of action of TCF21. TCF21 knock-down perturbed pathways that implicate TCF21 in recapitulation of disease progression in cultured human coronary artery smooth muscle cells (HCASMC). TCF21 knock-down network corresponds with TCF21 ChIP-Seq network and emphasizes the importance of collagen proteins in TCF21 modulation of CAD. TCF21 ChIP-Seq sites density elevates near CAD GWAS SNPs further emphasizing the role of TCF21 in CAD. DNase footprinting of TCF21 did not reveal clear pattern, unlike CTCF, implicating looser DNA complex association. TCF21 ChIP-Seq revealed tandem binding, short range DNA looping, as well as occupancy in AT-rich regions. TCF21 did not show clear clustering of nucleosomes, unlike CTCF. TCF21 marked distinct binding clusters near HCASMC, interchanging with SRF, CEBP1, and AP1 constituents JUN, JUND and FOS. Near CAD GWAS SNPs most dominant clusters consist of either TCF21, SRF or CEBP1. SRF binding eliminates, while TCF21 promotes open chromatin formation near CARDIOGRAMplusC4D CAD GWAS SNPs. Motif analysis revealed bimodal distribution of AP1 sites near TCF21 ChIP-Seq summits. Bi-modal interaction of AP1 with TCF21 was confirmed using JUN and FOS CHiP-Seq summits and localizes in open chromatin regions in HCASMC. In summary, genomics analysis of a CAD GWAS gene, TCF21, revealed alternating chromatin interaction of SRF and TCF21 and bimodal interaction with AP1 within the chromatin context, potentially implicating these two factors with CAD progression in HCASMC.