Molecular Interplay of the Non-coding RNA ANRIL and Methylated Histone H3 Lysine 27 by Polycomb CBX7 in Transcriptional Silencing of INK4a

By K. Yap, Side Li, Ana M. Muñoz-Cabello, S. Raguz, L. Zeng, S. Mujtaba, Jesús Gil, M. Walsh, Ming‐Ming Zhou. Molecules and Cells, 2010

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SUMMARY Expression of the INK4b/ARF/INK4a tumor suppressor locus in normal and cancerous cell growth is controlled by methylation of histone H3 at lysine 27 (H3K27me) as directed by the Polycomb group proteins. The antisense non-coding RNA ANRIL of the INK4b/ARF/INK4a locus is also important for expression of the protein-coding genes in cis, but its mechanism has remained elusive. Here we report that chromobox 7 (CBX7) within the Polycomb Repressive Complex 1 binds to ANRIL, and both CBX7 and ANRIL are found at elevated levels in prostate cancer tissues. In concert with H3K27me recognition, binding to RNA contributes to CBX7 function and disruption of either interaction impacts the ability of CBX7 to repress the INK4b/ARF/INK4a locus and control senescence. Structure-guided analysis reveals the molecular interplay between non-coding RNA and H3K27me as mediated by the conserved chromodomain. Our study suggests a new mechanism by which non-coding RNA participates directly in epigenetic transcriptional repression.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d5b40b9cb52a1b14396a996410d69e93c2e740f1

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Citations in the corpus

Long Noncoding RNAs: Past, Present, and Future (2013, background): “ANRIL, located in the p15/INK4B-p16/INK4Ap14/ARF tumor suppressor gene cluster, interacts with both the PRC1 component Cbx7 and the PRC2 component Suz12 (Yap et al. 2010; Kotake et al. 2011).”
Mechanisms of long noncoding RNA function in development and disease (2016, background): “When lncRNAs in plasma from myocardial infarction patients were profiled, a mitochondrial lncRNA named long intergenic noncoding RNA predicting cardiac remodeling (LIPCAR) was found to significantly correlate with mortality caused by CVD and could thus be considered as a biomarker [173].”
Control of Embryonic Stem Cell State (2011, background): “…complexes to the X-inactivation center X(ic), the kcnq1 domain, the INK4b/ARF/INK4a locus, the HOXD locus, andmany other genomic loci in ESCs and other cell types (Gupta et al., 2010; Pandey et al., 2008; Rinn et al., 2007; Tsai et al., 2010; Yap et al., 2010; Zhao et al., 2010; Zhao et al., 2008).”
Long non-coding RNAs: a new frontier in the study of human diseases. (2013, neutral): “3 Transcription regulation [17–20]”
Circular intronic long noncoding RNAs. (2013, background): “Several recent reports identified nonlinearized RNAs that are largely generated from back-spliced exons (Burd et al., 2010; Hansen et al., 2013; Jeck et al., 2013; Memczak et al., 2013; Salzman et al., 2012; Yap et al., 2010).”
Transcriptional Regulation and its Misregulation in Disease (2013, positive): “ANRIL functions by recruiting polycomb repressive complexes 1 and 2 (PRC1 and PRC2) and misregulation of ANRIL may lead to abnormal silencing of tumor suppressors and thus contribute to cancer progression (Kotake et al., 2011; Yap et al., 2010).”
How do lncRNAs regulate transcription? (2017, background): “The authors observed a possible ternary complex consisting of H3K27me3-ANRIL-CBX7 (92).”
Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches. (2016, neutral): “, H19, involved in imprinting; Anril, recruitment of PRC2 and PRC1; NEAT1, assembly of paraspeckles) (142, 179, 238, 298).”
Expression of Linear and Novel Circular Forms of an INK4/ARF-Associated Non-Coding RNA Correlates with Atherosclerosis Risk (2010, background): “However, this model would not easily explain the positive correlation we observed between the expression of coding INK4/ARF transcripts and proximal ANRIL exons (Figure 5A and Figure S6), as the 59end of ANRIL is reported to foster INK4/ARF repression [62].”
Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. (2010, positive): “been found to be crucial for repression of the p15/p16/ p19 locus (Yap et al., 2010).”
Molecular mechanisms of long noncoding RNAs (2011, background): “Work over the past few years has demonstrated a direct interaction between ANRIL and components from both PRC1 and PRC2 complexes (Kotake et al., 2011; Yap et al., 2010).”