p50-associated COX-2 extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-κB complexes.
p50-associated COX-2 extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-κB complexes.
复制标题
DOI：
10.7554/elife.01776
复制
发表时间：
2014-04-29
期刊：
影响因子：
7.7
通讯作者：
Emerson BM
中科院分区：
文献类型：
--
作者：
Krawczyk M;Emerson BM
COX-2的失控表达与多种人类癌症的发生、发展和转归有因果关系。我们描述了一个新的基础水平的转录控制的COX-2的表达。利用原代人乳腺上皮细胞和单核/巨噬细胞系，我们发现染色质边界/绝缘因子CTCF建立了一个开放的染色质结构域，并诱导了COX-2上游启动子区域内一个长的非编码RNA的表达。在诱导COX-2表达时，LncRNA与NF-κB的抑制性亚基p50结合，并将其与COX-2启动子阻断，潜在地促进了与具有激活能力的NF-κB p65/p50二聚体的相互作用。这使得p300组蛋白乙酰转移酶能够重新招募，组蛋白乙酰化和RNA聚合酶II起始复合体的组装在整个区域都得到了增加。我们的发现揭示了一种意想不到的通过lncRNA介导的抑制子阻断进行基因控制的机制，并发现COX-2-LncRNA PACER是炎症和癌症中COX-2调控的新的潜在靶点。DOI：http://dx.doi.org/10.7554/eLife.01776.001要产生蛋白质，细胞必须首先转录基因中的dna以产生信使rna分子，然后再翻译成蛋白质。然而，细胞也会产生其他类型的RNA分子，而这些分子不会变成蛋白质。例如，microRNAs作为蛋白质调节基因的表达，而其他被称为长非编码RNAs(LncRNAs)的RNA分子的作用还不是很清楚。现在，Krawczyk和Emerson发现了一种控制COX-2基因的lncRNA，该基因通常与乳腺癌、结肠癌、前列腺癌和肺癌有关。这种被称为PACER的RNA分子起源于COX-2基因起始处附近，但它不可能是信使RNA，因为它不包含制造COX-2蛋白的指令，而且它太长了，不可能是microRNA。进一步的实验表明，新发现的lncRNA激活了COX-2基因的表达。Krawczyk和Emerson发现，PACER吸引了一些酶，这些酶集中了需要激活的基因，从而增加了这些基因的转录，从而产生信使RNA。基因也可以通过与附近DNA结合的各种分子来开启和关闭，PACER通过阻止可能关闭它的分子来鼓励COX-2的激活。除了揭示lncRNAs的作用外，这些结果还表明，PACER可能是涉及COX-2基因的癌症的合适治疗靶点。DOI：http://dx.doi.org/10.7554/eLife.01776.002
Deregulated expression of COX-2 has been causally linked to development, progression, and outcome of several types of human cancer. We describe a novel fundamental level of transcriptional control of COX-2 expression. Using primary human mammary epithelial cells and monocyte/macrophage cell lines, we show that the chromatin boundary/insulator factor CTCF establishes an open chromatin domain and induces expression of a long non-coding RNA within the upstream promoter region of COX-2. Upon induction of COX-2 expression, the lncRNA associates with p50, a repressive subunit of NF-κB, and occludes it from the COX-2 promoter, potentially facilitating interaction with activation-competent NF-κB p65/p50 dimers. This enables recruitment of the p300 histone acetyltransferase, a domain-wide increase in histone acetylation and assembly of RNA Polymerase II initiation complexes. Our findings reveal an unexpected mechanism of gene control by lncRNA-mediated repressor occlusion and identify the COX-2-lncRNA, PACER, as a new potential target for COX-2-modulation in inflammation and cancer. DOI: http://dx.doi.org/10.7554/eLife.01776.001 To produce a protein a cell must first transcribe the DNA in a gene to make a messenger RNA molecule, which is then translated to make the protein. However, cells also produce other types of RNA molecules which do not become proteins. MicroRNAs, for example, regulate the expression of genes as proteins, while the role of other RNA molecules called long non-coding RNAs (lncRNAs) is not well understood. Now Krawczyk and Emerson have found an lncRNA that controls a gene called COX-2 that is often implicated in breast, colon, prostate, and lung cancer. This RNA molecule, which is called PACER, originates near the start of the COX-2 gene, but it cannot be messenger RNA because it does not contain the instructions to make the COX-2 protein, and it is too long to be a microRNA. Further experiments showed that the newly discovered lncRNA activates the expression of the COX-2 gene. Krawczyk and Emerson found that PACER attracts enzymes that spotlight genes that need to be activated, thus increasing the transcription of these genes to make messenger RNA. Genes can also be switched on and off by various molecules binding to nearby DNA, and PACER encourages the activation of COX-2 by keeping away the molecules that might switch it off. In addition to shedding new light on the role of lncRNAs, these results suggest that PACER could be a suitable therapeutic target in cancers that involve the COX-2 gene. DOI: http://dx.doi.org/10.7554/eLife.01776.002