Figure 4. Model for Nkx2–5 promoter-enhancer interaction in SHF-derived heart.

Shown is a conceptual model for promoter-enhancer interaction via multiple cardiac transcription factors, anchored on the SHF enhancer by DNA-bound Gata4/6 and Nkx2–5, and on the proximal promoter by DNA-bound Srf [15]. Assembly may culminate in the recruitment of Srf-associated myocardin and p300 acetylase, and may be further influenced by additional yet uncharacterized enhancer and/or promoter binding elements. Abbreviations: G4: Gata4; G6: Gata6; Nkx: Nkx2–5; Myoc: Myocardin; Srf: Srf. The figure includes combined data from this study, a previous study of conserved Nkx2–5 SHF regulation [15], and manually curated data from a genome-wide TF occupancy analysis [28] (gray, white and dark gray symbols), as noted at the bottom of the figure. Summary of ChIP data from these studies detecting TFs associated with SHF or promoter proximal amplicons is lifted at left for both fetal and adult stages. Not shown are YY1 and associated Bmp Smad1/4 complexes previously shown to mediate Bmp activation of SHF enhancers. Putative associations of Gata6, Myocardin and p300 with fetal SHF are inferred from prior functional activation data [10, 15].