Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression.
Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression.
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DOI：
10.1158/0008-5472.can-10-4379
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发表时间：
2011-08-15
期刊：
影响因子：
11.2
通讯作者：
Walsh MJ
中科院分区：
文献类型：
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作者：
Aguilo F;Zhou MM;Walsh MJ
多梳基团蛋白(PcG)是基因表达的转录抑制因子。最近发现，PcG通过直接与INK4基因座的长非编码RNA(LncRNA)转录反义非编码RNA(ANRIL)结合，在介导INK4b-ARF-INK4a基因座的抑制中发挥重要作用。INK4b-ARF-INK4a编码3种肿瘤抑制蛋白p15INK4b、p14ARF和p16INK4a，其转录是复制或癌基因诱导衰老的关键条件，并构成肿瘤生长的重要屏障。ANRIL基因以INK4b-ARF-INK4a基因簇的反义方向转录，不同的单核苷酸多态与多种疾病的易感性增加有关。虽然lncRNA介导的INK4b-ARF-INK4a基因的调控并不局限于ANRIL，但多梳抑制复合体-1(PRC1)和-2(PRC2)都与ANRIL相互作用，在INK4b-ARF-INK4a基因周围形成异染色质，导致其抑制。这一机制将为绕过衰老、维持干细胞和/或祖细胞群体的增殖需求或通过PcG复合体异常饱和INK4b-ARF-INK4a基因而不适当地导致肿瘤的发生提供更多的优势。在这篇综述中，我们总结了将PcG功能与ANRIL联系起来的潜在表观遗传学机制的最新发现，ANRIL施加基因沉默来控制细胞内稳态以及癌症的发展。
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, p15INK4b, p14ARF, and p16INK4a, 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.