Fig. 8

Mechanism of TCF21 and AP-1 epigenetic interactions in the context of CAD-associated genetic loci. TCF21 is a bHLH transcription factor associated with CAD as depicted here due to allelic variation in causal variants (Y), and its transcriptional regulatory function accounts for the attributable genetic risk at the 6q23.2 locus (brown oval). TCF21 binding is enriched in other CAD loci, where it interacts with AP-1 factors (JUN) that co-localize at these sites (gray oval). JUN promotes recruitment of HAT p300 to promote H3K27ac histone acetylation and open chromatin to recruit TFs, including TCF21, which in turn recruits HDACs 1 and 2 that function to oppose AP-1 effects. These epigenetic effects contribute in cis to the regulation of expression of the causal gene through alteration in the binding of the causal TF through CAD-associated variant Z (green circle) or other mechanisms of disease at this locus. Such interactions likely contribute to attributable genetic risk at both the TCF21 and downstream loci