Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15INK4B tumor suppressor gene

By Y. Kotake, T. Nakagawa, K. Kitagawa, Shohachi Suzuki, Ning Liu, M. Kitagawa, Y. Xiong. Oncogene, 2010

671 citations recorded by the source corpus.

A 42 kb region on human chromosome 9p21 encodes for three distinct tumor suppressors, p16INK4A, p14ARF and p15INK4B, and is altered in an estimated 30–40% of human tumors. The expression of the INK4A-ARF-INK4B gene cluster is silenced by polycomb during normal cell growth and is activated by oncogenic insults and during aging. How the polycomb is recruited to repress this gene cluster is unclear. Here, we show that expression of oncogenic Ras, which stimulates the expression of p15INK4B and p16INK4A, but not p14ARF, inhibits the expression of ANRIL (antisense non-coding RNA in the INK4 locus), a 3.8 kb-long non-coding RNA expressed in the opposite direction from INK4A-ARF-INK4B. We show that the p15INK4B locus is bound by SUZ12, a component of polycomb repression complex 2 (PRC2), and is H3K27-trimethylated. Notably, depletion of ANRIL disrupts the SUZ12 binding to the p15INK4B locus, increases the expression of p15INK4B, but not p16INK4A or p14ARF, and inhibits cellular proliferation. Finally, RNA immunoprecipitation demonstrates that ANRIL binds to SUZ12 in vivo. Collectively, these results suggest a model in which ANRIL binds to and recruits PRC2 to repress the expression of p15INK4B locus.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/dd72b17446a66cafecdf8fb1fa7f2178230119d8

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Citations in the corpus

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).”
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).”
The rise of regulatory RNA (2014, background): “…266–268 and vernalization in plants 269 , with subsequent studies showing that intergenic and antisense RNAs bind to polycomb chromatin repressive complexes 194,270–272 , to trithorax chromatin activating complexes and activated forms of histones 207 , and to DNA methyltransferases 201,273,274 .”