长链非编码 RNA p21 通过顺式激活 p21 促进多梳靶基因的表达并加强 G1/S 检验点。
LincRNA-p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint.
机构信息
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142, USA.
Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
出版信息
Mol Cell. 2014 Jun 5;54(5):777-90. doi: 10.1016/j.molcel.2014.04.025. Epub 2014 May 22.
The p53-regulated long noncoding RNA lincRNA-p21 has been proposed to act in trans via several mechanisms ranging from repressing genes in the p53 transcriptional network to regulating mRNA translation and protein stability. To further examine lincRNA-p21 function, we generated a conditional knockout mouse model. We find that lincRNA-p21 predominantly functions in cis to activate expression of its neighboring gene, p21. Mechanistically, we show that lincRNA-p21 acts in concert with hnRNP-K as a coactivator for p53-dependent p21 transcription. Additional phenotypes of lincRNA-p21 deficiency could be attributed to diminished p21 levels, including deregulated expression and altered chromatin state of some Polycomb target genes, a defective G1/S checkpoint, increased proliferation rates, and enhanced reprogramming efficiency. These findings indicate that lincRNA-p21 affects global gene expression and influences the p53 tumor suppressor pathway by acting in cis as a locus-restricted coactivator for p53-mediated p21 expression.
p53 调控的长非编码 RNA lincRNA-p21 被提出通过几种机制发挥反式作用，范围从抑制 p53 转录网络中的基因到调节 mRNA 翻译和蛋白质稳定性。为了进一步研究 lincRNA-p21 的功能，我们生成了一个条件性敲除小鼠模型。我们发现 lincRNA-p21 主要在顺式作用中激活其邻近基因 p21 的表达。从机制上讲，我们表明 lincRNA-p21 与 hnRNP-K 一起作为 p53 依赖性 p21 转录的共激活因子发挥作用。lincRNA-p21 缺失的其他表型可能归因于 p21 水平降低，包括一些 Polycomb 靶基因的表达失调和染色质状态改变、G1/S 检查点缺陷、增殖率增加和增强的重编程效率。这些发现表明，lincRNA-p21 通过作为 p53 介导的 p21 表达的局域限制共激活因子在顺式作用中影响全局基因表达，并影响 p53 肿瘤抑制途径。
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