Epigenetic regulation of the INK4b-ARF-INK4a locus: in sickness and in health

Abstract

The INK4b-ARF-INK4a locus encodes for two cyclin-dependent kinase inhibitors, p15(INK4b) and p16(INK4a) and a regulator of the p53 pathway, ARF. In addition ANRIL, a non-coding RNA, is also transcribed from the locus. ARF, p15(INK4b) and p16(INK4a) are well-established tumor suppressors which function is frequently disabled in human cancers. Recent studies showed that single nucleotide polymorphisms mapping in the vicinity of ANRIL are linked to a wide spectrum of conditions, including cardiovascular disease, ischemic stroke, type 2 diabetes, frailty and Alzheimer's disease. The INK4b-ARF-INK4a locus is regulated by Polycomb repressive complexes (PRCs), and its expression can be invoked by activating signals. Other epigenetic modifiers such as the histone demethylases JMJD3 and JHDM1B, the SWI/SNF chromatin remodeling complex and DNA methyltransferases regulate the locus interplaying with PRCs. In view of the intimate involvement of the INK4b-ARF-INK4a locus on disease, to understand its regulation is the first step for manipulate it to therapeutic benefit.

Figure 1

Organization of the INK4b-ARF-INK4a locus and disease-associated SNPs. Genetic structure of the human INK4b-ARF-INK4a locus. The coding exons are shown in colors and non-coding exons are shown in light gray for ANRIL and dark gray for the other genes of the locus. The approximate position of single nucleotide polymorphisms (SNPs) associated with disease states is indicated by blue arrows. SNPs associated with type 2 diabetes mellitus (D), vascular heart disease (H) and frailty (F) are indicated. Map is not drawn to scale and positions are approximate.

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 p15^INK4b 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.