The long non-coding RNA ERIC is regulated by E2F and modulates the cellular response to DNA damage.
The long non-coding RNA ERIC is regulated by E2F and modulates the cellular response to DNA damage.
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DOI：
10.1186/1476-4598-12-131
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发表时间：
2013-10-29
期刊：
影响因子：
37.3
通讯作者：
Ginsberg D
中科院分区：
文献类型：
--
作者：
Feldstein O;Nizri T;Doniger T;Jacob J;Rechavi G;Ginsberg D
人类基因组编码数千个独特的长非编码 RNA (lncRNA)，这些转录物正在成为基因表达和细胞命运的关键调节因子。然而，它们表达的转录调控尚不完全清楚。关键转录因子 E2F1 可诱导增殖和细胞死亡，是肿瘤抑制因子 RB 的关键下游靶标。视网膜母细胞瘤通路在人类肿瘤中通常失活，导致 E2F 活性失调。在这里，我们报告 lncRNA XLOC 006942（我们将其命名为 ERIC）受 E2F1 调控，并且很可能也受 E2F3 调控。我们发现，外源 E2F1、E2F3 或内源 E2F 激活后 ERIC 的表达水平升高。此外，E2F1 或 E2F3 的敲低会降低 ERIC 水平，并且内源性 E2F1 会结合 ERIC 的启动子。 ERIC 的表达受细胞周期调节，并以 E2F1 依赖性方式在 G1 达到峰值。抑制 ERIC 表达会增加 E2F1 介导的细胞凋亡，表明 E2F1 和 ERIC 构成调节 E2F1 活性的负反馈环。此外，化疗药物依托泊苷对DNA造成损伤后，ERIC水平升高，并且抑制ERIC表达可增强依托泊苷诱导的细胞凋亡。我们的数据表明 ERIC 是一种新型 lncRNA，受 E2F 转录调节，并限制 E2F1 以及 DNA 损伤诱导的细胞凋亡。
The human genome encodes thousands of unique long non-coding RNAs (lncRNAs), and these transcripts are emerging as critical regulators of gene expression and cell fate. However, the transcriptional regulation of their expression is not fully understood. The pivotal transcription factor E2F1 which can induce both proliferation and cell death, is a critical downstream target of the tumor suppressor, RB. The retinoblastoma pathway is often inactivated in human tumors resulting in deregulated E2F activity. Here, we report that lncRNA XLOC 006942, which we named ERIC, is regulated by E2F1 and, most probably, also E2F3. We show that expression levels of ERIC were elevated upon activation of exogenous E2F1, E2F3 or endogenous E2Fs. Moreover, knockdown of either E2F1 or E2F3 reduced ERIC levels and endogenous E2F1 binds ERIC’s promoter. Expression of ERIC was cell cycle regulated and peaked in G1 in an E2F1-dependent manner. Inhibition of ERIC expression increased E2F1-mediated apoptosis, suggesting that E2F1 and ERIC constitute a negative feedback loop that modulates E2F1 activity. Furthermore, ERIC levels were increased following DNA damage by the chemotherapeutic drug Etoposide, and inhibition of ERIC expression enhanced Etoposide -induced apoptosis. Our data identify ERIC as a novel lncRNA that is transcriptionally regulated by E2Fs, and restricts apoptosis induced by E2F1, as well as by DNA damage.
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影响因子：
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