Local regulation of gene expression by lncRNA promoters, transcription and splicing.
Local regulation of gene expression by lncRNA promoters, transcription and splicing.
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DOI：
10.1038/nature20149
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发表时间：
2016-11-17
期刊：
影响因子：
64.8
通讯作者：
Lander ES
中科院分区：
文献类型：
--
作者：
Engreitz JM;Haines JE;Perez EM;Munson G;Chen J;Kane M;McDonel PE;Guttman M;Lander ES
哺乳动物基因组普遍转录以产生数千个长非编码RNA（lncRNA）。这些lncRNA中的一些已被证明通过RNA-蛋白质相互作用招募调节复合物以影响附近基因的表达，并且已经表明许多其他lncRNA类似地充当局部调节剂。这种局部功能可以解释lncRNA表达通常与附近基因表达相关的观察结果。然而，这种相关性一直具有挑战性的剖析，也可能是由于过程中，不介导的lncRNA转录本本身。例如，已经提出一些基因启动子具有作为增强子的双重功能，并且已经提出转录过程本身通过募集活化因子或重塑核小体来促进基因调控。在这里，我们使用遗传操作来解剖12个产生lncRNA的基因组位点，发现其中5个位点影响顺式相邻基因的表达。令人惊讶的是，这些效应都不需要特定的lncRNA转录本本身，而是涉及与其产生相关的一般过程，包括基因启动子的增强子样活性，转录过程和转录本的剪接。重要的是，这种影响并不局限于lncRNA基因座：我们发现6个蛋白质编码基因座中有4个同样影响相邻基因座的表达。这些结果表明，相邻基因之间的“串扰”是一种普遍现象，可能涉及多种机制和顺式调控信号，包括RNA剪接位点的新作用。这些机制可以解释一些产生lncRNA的基因组位点的功能和进化，并广泛地促进编码和非编码基因的调节。
Mammalian genomes are pervasively transcribed to produce thousands of long noncoding RNAs (lncRNAs). A few of these lncRNAs have been shown to recruit regulatory complexes through RNA-protein interactions to influence the expression of nearby genes, and it has been suggested that many other lncRNAs similarly act as local regulators. Such local functions could explain the observation that lncRNA expression is often correlated with the expression of nearby genes. However, such correlations have been challenging to dissect and could alternatively result from processes that are not mediated by the lncRNA transcripts themselves. For example, some gene promoters have been proposed to have dual functions as enhancers, and the process of transcription per se has been proposed to contribute to gene regulation by recruiting activating factors or remodeling nucleosomes. Here we used genetic manipulations to dissect 12 genomic loci that produce lncRNAs and found that 5 of these loci influence the expression of a neighboring gene in cis. Surprisingly, none of these effects required the specific lncRNA transcripts themselves and instead involved general processes associated with their production, including enhancer-like activity of gene promoters, the process of transcription, and the splicing of the transcript. Importantly, such effects were not limited to lncRNA loci: we found that 4 of 6 protein-coding loci similarly influenced the expression of a neighbor. These results demonstrate that ‘crosstalk’ among neighboring genes is a prevalent phenomenon that can involve multiple mechanisms and cis regulatory signals, including a novel role for RNA splice sites. These mechanisms may explain the function and evolution of some genomic loci that produce lncRNAs and broadly contribute to the regulation of both coding and noncoding genes.
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