Novel long noncoding RNAs are regulated by angiotensin II in vascular smooth muscle cells.
Novel long noncoding RNAs are regulated by angiotensin II in vascular smooth muscle cells.
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DOI：
10.1161/circresaha.112.300849
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发表时间：
2013-07-19
影响因子：
20.1
通讯作者：
Natarajan R
中科院分区：
文献类型：
--
作者：
Leung A;Trac C;Jin W;Lanting L;Akbany A;Sætrom P;Schones DE;Natarajan R
血管紧张素II（Ang II）作用的失调可导致动脉粥样硬化和高血压。评估血管平滑肌细胞（VSMCs）中对Ang II的转录组反应对于了解Ang II调控的基因网络非常重要，这可能会发现以前未确定的机制和新的治疗靶点。使用转录组和表观基因组分析鉴定大鼠VSMCs中对Ang II应答的所有转录物，包括新型蛋白编码和长非编码RNA，差异表达。从RNA-seq的转录物的从头组装揭示了新的蛋白质编码和长非编码RNA（lncRNA）。这些新转录物的大多数基因组位点富含组蛋白H3赖氨酸-4-三甲基化和组蛋白H3赖氨酸-36-三甲基化，这两种染色质修饰发现于活跃转录区域，进一步证明这些是真正的转录物。转录丰度分析鉴定了所有由Ang II调节的蛋白质编码和lncRNA。我们进一步发现，一种Ang II调节的lncRNA作为miR-221和miR-222的宿主转录物发挥功能，这两种miRNA与细胞增殖有关。此外，siRNA介导的Lnc-Ang362敲低降低了VSMC的增殖。这些数据为血管紧张素II在血管平滑肌细胞中的表观基因组学和转录组学作用提供了新的见解。他们首次鉴定了Ang II调节的lncRNA，这表明这些lncRNA在介导对Ang II的细胞应答中的功能作用。此外，我们确定了一个血管紧张素II调节lncRNA是负责生产两个涉及VSMC增殖的miRNA。这些新发现的非编码转录本可作为血管紧张素II相关心血管疾病的新的治疗靶点。
Misregulation of angiotensin II (Ang II) actions can lead to atherosclerosis and hypertension. Evaluating transcriptomic responses to Ang II in vascular smooth muscle cells (VSMCs) is important to understand the gene networks regulated by Ang II which might uncover previously unidentified mechanisms and new therapeutic targets. To identify all transcripts, including novel protein-coding and long non-coding RNAs, differentially expressed in response to Ang II in rat VSMCs using transcriptome and epigenome profiling. De novo assembly of transcripts from RNA-seq revealed novel protein-coding and long non-coding RNAs (lncRNAs). The majority of the genomic loci of these novel transcripts are enriched for histone H3 lysine-4-trimethylation and histone H3 lysine-36-trimethylation, two chromatin modifications found at actively transcribed regions, providing further evidence that these are bonafide transcripts. Analysis of transcript abundance identified all protein-coding and lncRNAs regulated by Ang II. We further discovered that one Ang II-regulated lncRNA functions as the host transcript for miR-221 and miR-222, two miRNAs implicated in cell proliferation. Additionally, siRNA-mediated knockdown of Lnc-Ang362 reduced proliferation of VSMCs. These data provide novel insights into the epigenomic and transcriptomic effects of Ang II in VSMCs. They provide the first identification of Ang II-regulated lncRNAs, which suggests functional roles for these lncRNAs in mediating cellular responses to Ang II. Furthermore, we identify one Ang IIregulated lncRNA that is responsible for the production of two miRNAs implicated in VSMC proliferation. These newly identified non-coding transcripts could be exploited as novel therapeutic targets for Ang II-associated cardiovascular diseases.