In Vivo Characterization of Linc-p21 Reveals Functional cis-Regulatory DNA Elements.
In Vivo Characterization of Linc-p21 Reveals Functional cis-Regulatory DNA Elements.
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DOI：
10.1016/j.celrep.2016.07.050
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发表时间：
2016-08-23
期刊：
影响因子：
8.8
通讯作者：
Rinn JL
中科院分区：
文献类型：
--
作者：
Groff AF;Sanchez-Gomez DB;Soruco MML;Gerhardinger C;Barutcu AR;Li E;Elcavage L;Plana O;Sanchez LV;Lee JC;Sauvageau M;Rinn JL
Linc-p21基因座编码长的非编码RNA，在p53信号传导、细胞周期调节和肿瘤抑制中起重要作用。然而，尽管进行了广泛的研究，关于其作用机制仍存在混淆：活性是由转录本以反式、顺式或潜在的功能增强子驱动的？在这里，使用基因敲除小鼠模型和大规模平行增强子测定，我们描绘了在这个位点的功能元件。我们观察到，即使在没有检测到Linc-p21转录的组织中，该位点的缺失也会显著影响局部基因表达，包括细胞周期调节因子Cdkn 1a。为了表征这种不依赖于RNA的调节作用，我们系统地询问了核苷酸分辨率下增强子活性的潜在DNA序列，并证实了多个增强子元件的存在。总之，这些数据表明，在体内，由Linc-p21介导的顺式调节作用，在转录的存在或不存在下，是由于DNA增强子元件。使用敲除小鼠模型和大规模平行报告基因测定，Groff等人表明，先前被认为产生顺式作用lincRNA的lincp 21基因实际上包含多个增强子元件，这些元件直接负责调节附近基因（包括Cdkn 1a）的转录。
The Linc-p21 locus, encoding a long non-coding RNA, plays an important role in p53 signalling, cell cycle regulation, and tumour suppression. However, despite extensive study, confusion exists regarding its mechanism of action: is activity driven by the transcript acting in trans, in cis, or by an underlying functional enhancer? Here, using a knockout mouse model and a massively parallel enhancer assay, we delineate the functional elements at this locus. We observe that even in tissues with no detectable Linc-p21 transcript, deletion of the locus significantly affects local gene expression, including of the cell cycle regulator Cdkn1a. To characterize this RNA-independent regulatory effect, we systematically interrogated the underlying DNA sequence for enhancer activity at nucleotide resolution, and confirmed the existence of multiple enhancer elements. Together, these data suggest that, in vivo, the cis-regulatory effects mediated by Linc-p21, in the presence or absence of transcription, are due to DNA enhancer elements. Using a knockout mouse model and massively parallel reporter assay, Groff et al. show that the lincp21 gene, which was previously thought to produce a cis-acting lincRNA, actually contains multiple enhancer elements that are directly responsible for regulating transcription of nearby genes, including Cdkn1a.
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影响因子：
64.5
作者：
Huarte M;Guttman M;Feldser D;Garber M;Koziol MJ;Kenzelmann-Broz D;Khalil AM;Zuk O;Amit I;Rabani M;Attardi LD;Regev A;Lander ES;Jacks T;Rinn JL
通讯作者：
Rinn JL
影响因子：
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通讯作者：
Houlston RS
影响因子：
30.8
作者：
Mifsud, Borbala;Tavares-Cadete, Filipe;Osborne, Cameron S.
通讯作者：
Osborne, Cameron S.
影响因子：
56.9
作者：
HALEVY, O;NOVITCH, BG;LASSAR, AB
通讯作者：
LASSAR, AB
影响因子：
10.5
作者：
Link, Nichole;Kurtz, Paula;Abrams, John M.
通讯作者：
Abrams, John M.