The long noncoding RNA SPRIGHTLY acts as an intranuclear organizing hub for pre-mRNA molecules.
The long noncoding RNA SPRIGHTLY acts as an intranuclear organizing hub for pre-mRNA molecules.
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DOI：
10.1126/sciadv.1602505
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发表时间：
2017-05
期刊：
影响因子：
13.6
通讯作者：
Perera RJ
中科院分区：
文献类型：
--
作者：
Lee B;Sahoo A;Marchica J;Holzhauser E;Chen X;Li JL;Seki T;Govindarajan SS;Markey FB;Batish M;Lokhande SJ;Zhang S;Ray A;Perera RJ
LncRNA与其靶mRNAs的未处理的mRNA前体的内含子区域活跃地相互作用。长非编码RNA(LncRNA)分子影响癌症状态的分子机制尚不清楚。果蝇同源基因Sprouty-4内含子中编码的活泼的lncRNA的异常表达与包括人类黑色素瘤在内的多种癌症有关。我们通过SHAPE-SEQ和dChIRP证明了RNA二级结构中有一个核心的伪节结构域。这个lncRNA与六个前mRNAs的内含子区域相互作用：SOX5、SMYD3、SND1、MEOX2、DCTN6和RASAL2，所有这些都具有与癌症相关的功能。在黑色素瘤细胞中，CRISPR(簇规则间隔短回文重复序列)/Cas9的半合子基因敲除显著降低了lncRNA水平，同时降低了其相互作用的Pre-mRNA分子的水平，并降低了细胞的锚定非依赖性生长速度和小鼠移植瘤的体内生长速度。这些结果首次证明了LncRNA在促进人类黑色素瘤中癌症相关基因表达方面的三维协调作用。
The lncRNA SPRIGHTLY interacts with the intronic regions of unprocessed mRNA precursors of its target mRNAs. Molecular mechanisms by which long noncoding RNA (lncRNA) molecules may influence cancerous condition are poorly understood. The aberrant expression of SPRIGHTLY lncRNA, encoded within the drosophila gene homolog Sprouty-4 intron, is correlated with a variety of cancers, including human melanomas. We demonstrate by SHAPE-seq and dChIRP that SPRIGHTLY RNA secondary structure has a core pseudoknotted domain. This lncRNA interacts with the intronic regions of six pre-mRNAs: SOX5, SMYD3, SND1, MEOX2, DCTN6, and RASAL2, all of which have cancer-related functions. Hemizygous knockout of SPRIGHTLY by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 in melanoma cells significantly decreases SPRIGHTLY lncRNA levels, simultaneously decreases the levels of its interacting pre-mRNA molecules, and decreases anchorage-independent growth rate of cells and the rate of in vivo tumor growth in mouse xenografts. These results provide the first demonstration of an lncRNA’s three-dimensional coordinating role in facilitating cancer-related gene expression in human melanomas.