Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene.
Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene.
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DOI：
10.1038/onc.2010.568
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发表时间：
2011-04-21
期刊：
影响因子：
8
通讯作者：
Xiong, Y.
中科院分区：
文献类型：
--
作者：
Kotake, Y.;Nakagawa, T.;Kitagawa, K.;Suzuki, S.;Liu, N.;Kitagawa, M.;Xiong, Y.
人类染色体9 p21上的42 kb区域编码三种不同的肿瘤抑制因子p16 INK 4A、p14 ARF和p15 INK 4 B，并且在估计30-40%的人类肿瘤中发生改变。INK 4A-ARF-INK 4 B基因簇的表达在正常细胞生长期间被polycomb沉默，并且在致癌损伤和衰老期间被激活。polycomb是如何被招募来抑制这个基因簇的还不清楚。在这里，我们表明，致癌Ras的表达，刺激p15 INK 4 B和p16 INK 4A的表达，但不是p14 ARF，抑制ANRIL（INK 4基因座的反义非编码RNA）的表达，一个3.8 kb长的非编码RNA在INK 4A-ARF-INK 4 B的相反方向表达。我们发现，p15 INK 4 B位点结合SUZ 12，一个组成部分的polycomb阻遏复合物2（PRC 2），是H3 K27-三甲基化。值得注意的是，ANRIL的缺失破坏了SUZ 12与p15 INK 4 B基因座的结合，增加了p15 INK 4 B的表达，但不增加p16 INK 4A或p14 ARF的表达，并抑制了细胞增殖。最后，RNA免疫沉淀证明ANRIL在体内与SUZ 12结合。总之，这些结果提示了ANRIL结合并募集PRC 2以抑制p15 INK 4 B位点表达的模型。
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.
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影响因子：
11.2
作者：
Kotake Y;Zeng Y;Xiong Y
通讯作者：
Xiong Y
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
10.5
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian
影响因子：
11.8
作者：
Terranova, Rrni;Yokobayashi, Shihori;Peters, Antoine H. F. M.
通讯作者：
Peters, Antoine H. F. M.
影响因子：
5.3
作者：
Malumbres, M;Perez de Castro, I;Pellicer, A
通讯作者：
Pellicer, A