The many faces of H3.3 in regulating chromatin in embryonic stem cells and beyond

H3.3 is a highly conserved nonreplicative histone variant. H3.3 is enriched in promoters and enhancers of active genes, but it is also found within suppressed heterochromatin, mostly around telomeres. Accordingly, H3.3 is associated with seemingly contradicting functions: It is involved in development, differentiation, reprogramming, and cell fate, as well as in heterochromatin formation and maintenance, and the silencing of developmental genes. The emerging view is that different cellular contexts and histone modifications can promote opposing functions for H3.3. Here, we aim to provide an update with a focus on H3.3 functions in early mammalian development, considering the context of embryonic stem cell maintenance and differentiation, to finally conclude with emerging roles in cancer development and cell fate transition and maintenance.