Figure 1:

Combinatorial control of ATF4 activity. Schematized, partial depiction of the proximal promoter fragment of the Osteocalcin gene: the RUNX2 binding site, OSE2 (Osteoblast Specific Element 2) and the ATF4 binding site, OSE1 (Osteoblast Specific Element 1) are shown. A. activating combinations: i) dimerization of ATF4 with C/EBPβ allows formation of a complex with RUNX2 to increase Osteocalcin expression; ii) TFIIAγ acts as a protein bridge between ATF4, RUNX2, and general transcription factors (GTFs); iii) SATB2 stabilizes the interaction of RUNX2 and ATF4 with DNA, leading to enhanced transcription; iv) transcriptional cooperativity between FoxO1 and ATF4. B. inhibitory combinations: i, ii) interaction of ATF4 with ICER or FIAT forms inactive dimers that cannot bind the OSE1 site; iii) steric hindrance at the proximal promoter caused by the binding of αNAC prevents ATF4 dimers from binding to the OSE1 element; iv) αNAC or FIAT could recruit repressor molecules to the promoter to block ATF4 activity.