Based on studies in mice, RUNX2 forms a complex with HEY2 (HRT2), a product of the NOTCH1 target gene. Binding to HEY2 inhibits RUNX2-mediated transcriptional activation of the BGLAP (Osteocalcin) gene (Garg et al. 2005). Other NOTCH1 targets, HEY1 and HES1, can also bind to RUNX2 and inhibit RUNX2 transcriptional activity (Hilton et al. 2008). NOTCH1 mutations cause severe aortic valve calcification in humans, which may be due to impaired repression of RUNX2-mediated transcription (Garg et al. 2005). NOTCH-mediated inhibition of RUNX2 transcriptional activity is also implicated in the maintenance of mesenchymal progenitors in the bone marrow by suppression of osteoblast differentiation (Hilton et al. 2008).
NOTCH1 may also inhibit RUNX2-mediated activation of target promoters by formation of a complex between RUNX2 and NOTCH1 intracellular domain (NICD1) (Engin et al. 2008).