Figure 2.
Epigenetic regulation of the INK4b-ARF-INK4a locus. Cartoon summarizing different epigenetic mechanisms regulating the locus. Epigenetic silencing of the locus in normal cells is mediated by Polycomb repressive complexes (PRCs). In tumorigenesis, methylation of the INK4a or INK4b promoters is often observed. Chromatin remodeling by the SWI /SNF5 complex result in displacement of PRCs complexes and locus activation. The histone demethylases Jhdm1b regulate the expression of p15INK4b while JMJD3 counteract the effects of H3K27me3 marks and PRC-mediated silencing. MAPKAP phosphorylation of Bmi1 results in PRC1 displacement from chromatin. Recent evidence suggests that ANRIL and maybe other ncRNAs could regulate the locus. We still do not understand how transcription factors interplay with this epigenetic machinery to regulate the locus. Epigenetic modifiers are shown in color. PRCs, Polycomb repressive complexes; DNMTs, DNA methyl transferases; TF s, transcription factors. Black lines show relation; red arrows, activation; green arrows, inhibition. Map is not drawn to scale and positions are approximate.