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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.

SUBMITTER: Aguilo F

PROVIDER: S-EPMC3339196 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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

Aguilo Francesca F Zhou Ming-Ming MM Walsh Martin J MJ

Cancer research 20110809 16

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 constitut ...[more]

PMID: 21828241

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Project description:BACKGROUND: The INK4b-ARF-INK4a tumour suppressor locus controls the balance between progenitor cell renewal and cancer. In this study, we investigated how higher-order chromatin structure modulates differential expression of the human INK4b-ARF-INK4a locus during progenitor cell differentiation, cellular ageing and senescence of cancer cells. RESULTS: We found that INK4b and INK4a, but not ARF, are upregulated following the differentiation of haematopoietic progenitor cells, in ageing fibroblasts and in senescing malignant rhabdoid tumour cells. To investigate the underlying molecular mechanism we analysed binding of polycomb group (PcG) repressive complexes (PRCs) and the spatial organization of the INK4b-ARF-INK4a locus. In agreement with differential derepression, PcG protein binding across the locus is discontinuous. As we described earlier, PcG repressors bind the INK4a promoter, but not ARF. Here, we identified a second peak of PcG binding that is located approximately 3 kb upstream of the INK4b promoter. During progenitor cell differentiation and ageing, PcG silencer EZH2 attenuates, causing loss of PRC binding and transcriptional activation of INK4b and INK4a. The expression pattern of the locus is reflected by its organization in space. In the repressed state, the PRC-binding regions are in close proximity, while the intervening chromatin harbouring ARF loops out. Down regulation of EZH2 causes release of the approximately 35 kb repressive chromatin loop and induction of both INK4a and INK4b, whereas ARF expression remains unaltered. CONCLUSION: PcG silencers bind and coordinately regulate INK4b and INK4a, but not ARF, during a variety of physiological processes. Developmentally regulated EZH2 levels are one of the factors that can determine the higher order chromatin structure and expression pattern of the INK4b-ARF-INK4a locus, coupling human progenitor cell differentiation to proliferation control. Our results revealed a chromatin looping mechanism of long-range control and argue against models involving homogeneous spreading of PcG silencers across the INK4b-ARF-INK4a locus.

Dataset Information

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

Publications

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

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