Competition between H3.3 and CENP-A for chaperone complex ATRX/DAXX. Normally CENP-A is directed to the centromere by its dedicated chaperone HJURP via a tightly regulated pathway (see text), whereas H3.3 is incorporated in various locations on the genome by its chaperones HIRA and ATRX/DAXX. HIRA directs H3.3 to chromatin and is required for establishing H3K27me3 at promoters of developmentally regulated genes in embryonic stem cells via the polycomb complex [120] as well as active genes [121,122]. On the other hand, ATRX/DAXX directs H3.3 to pericentric, subtelomeric, and interstitial heterochromatin [33,119]. In mice, H3.3 is encoded by two genes (H3f3a and H3f3b). Knock-out of H3f3b results in ectopic localization of CENP-A [39]. Overexpression of CENP-A also results in ectopic localization in human cell lines. In the latter case CENP-A is predominantly incorporated as a heterotypic CENP-A/H3.3 nucleosome via ATRX/DAXX chaperones [48]. These observations argue for a model where each gene product goes to specific sites in the genomes based on its association with each specific chaperone.