Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression

Abstract

Polycomb group proteins (PcG) function as transcriptional repressors of gene expression. The important role of PcG in mediating repression of the INK4b-ARF-INK4a locus, by directly binding to the long noncoding RNA (lncRNA) transcript antisense noncoding RNA in the INK4 locus (ANRIL), was recently shown. INK4b-ARF-INK4a encodes 3 tumor-suppressor proteins, p15(INK4b), p14(ARF), and p16(INK4a), and its transcription is a key requirement for replicative or oncogene-induced senescence and constitutes an important barrier for tumor growth. ANRIL gene is transcribed in the antisense orientation of the INK4b-ARF-INK4a gene cluster, and different single-nucleotide polymorphisms are associated with increased susceptibility to several diseases. Although lncRNA-mediated regulation of INK4b-ARF-INK4a gene is not restricted to ANRIL, both polycomb repressive complex-1 (PRC1) and -2 (PRC2) interact with ANRIL to form heterochromatin surrounding the INK4b-ARF-INK4a locus, leading to its repression. This mechanism would provide an increased advantage for bypassing senescence, sustaining the requirements for the proliferation of stem and/or progenitor cell populations or inappropriately leading to oncogenesis through the aberrant saturation of the INK4b-ARF-INK4a locus by PcG complexes. In this review, we summarize recent findings on the underlying epigenetic mechanisms that link PcG function with ANRIL, which impose gene silencing to control cellular homeostasis as well as cancer development.

Figure 1

Model of ANRIL lncRNA-mediated p16^INK4a gene repression by the PRC complex. The nascent ANRIL lncRNA is transcribed by RNA polymerase II at the TSS in the p16^INK4a gene and associates with Suz12 to recruit PRC2 complex and initiate H3K27me3. Subsequently, PRC1 is recruited by ANRIL via direct binding with CBX7 chromodomain, providing another docking site to bind H3K27me3 and allowing H2AK119ub1, which in turn results in the maintenance of epigenetic repression. As a consequence of the INK4b-ARF-INK4a locus silencing, cell proliferation is triggered, whereas senescence is inhibited.