PHF8 Mediates Histone H4 Lysine 20 Demethylation Events Involved in Cell Cycle Progression

While reversible histone modifications are linked to an ever-expanding range of biological functions1–5, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here, we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while utilizing multiple substrates, including H3K9me(1/2) and H3K27me(2), also functions as an H4K20me(1) demethylase. PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me(2/3) and controls G1/S transition in conjunction with E2F1, HCF-1 and Set1A, at least in part, by removing the repressive H4K20me(1) mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me(1) during early mitosis, which might represent a component of the Condensin II loading process. Accordingly, the HEAT repeat clusters in two non-SMC Condensin II subunits, N-CAPD3 and N-CAPG2, are capable of recognizing H4K20me(1), and ChIP-seq. analysis demonstrate a significant overlap of Condensin II and H4K20me(1) sites in mitotic HeLa cells. Thus, the identification and characterization of the first H4K20me(1) demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression.