Epigenetics meets metabolism through PHB-mediated histone H3.3 deposition by HIRA

The regulation of chromatin, the histone-mediated packaged form of DNA in the eukaryotic nucleus, underlies the epigenetic control of gene expression (1). Epigenetic regulators include DNA and histone modifying enzymes, proteins that specifically target native or modified DNA and histones, non-coding RNA molecules and histone chaperone and ATP-dependent remodeling complexes that deposit, move or evict canonical or variant histones. While the mode of chromatin targeting of many epigenetic factors has been delineated (2), the mechanism of histone chaperone complex recruitment for specific histone deposition is not understood. One such histone chaperone complex contains the proteins HIRA, Ubinuclein-1 (UBN1), CABIN1 and transiently associated ASF1 to deposit the histone H3.3 variant at the promoters of active and poised genes, bodies of active genes, developmental genes, active enhancers and sites of DNA and chromatin damage and repair (3) (Figure 1).