Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs.
Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs.
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DOI：
10.1371/journal.pgen.1003470
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发表时间：
2013-04
期刊：
影响因子：
4.5
通讯作者：
Feschotte C
中科院分区：
文献类型：
--
作者：
Kapusta A;Kronenberg Z;Lynch VJ;Zhuo X;Ramsay L;Bourque G;Yandell M;Feschotte C
脊椎动物基因组学的进展已经发现了数千个编码长非编码RNA（lncRNA）的基因座。虽然在阐明lncRNA的调节功能方面取得了进展，但对其起源和进化知之甚少。在这里，我们探讨的贡献转座因子（TE）的化妆和调节lncRNA在人类，小鼠和斑马鱼。令人惊讶的是，TE出现在超过三分之二的成熟lncRNA转录物中，占总lncRNA序列的相当大一部分（人类约30%），而它们很少出现在蛋白质编码转录物中。虽然TE对lncRNA外显子的贡献低于预期，但几个TE家族强烈富集lncRNA。嵌入lncRNA中的TE的覆盖范围和类型也存在很大的种间差异，部分反映了所调查基因组的TE景观的差异。在人类中，lncRNA中的TE序列在比它们的非TE序列、比它们的内含子TE或比随机DNA更大的进化约束下进化。与功能限制一致，我们发现TE贡献了许多lncRNA的生物发生所必需的信号，包括人类中用于转录起始、剪接或聚腺苷酸化的约30，000个独特位点。此外，我们还鉴定了135，000个标记为开放染色质的TE，位于lncRNA基因上游10 kb内。这些标记在一种细胞类型中的密度与相同细胞类型中下游lncRNA的表达升高相关，表明这些TE有助于顺式调节。这些全球趋势在几种具有既定功能的lncRNA中得到了概括。最后，嵌入lncRNA中的TE的子集经历RNA编辑，并预测形成可能对功能重要的二级结构。总之，TE在lncRNA中几乎是普遍存在的，并且在脊椎动物lncRNA库的谱系特异性多样化中发挥了重要作用。在人类和其他脊椎动物的基因组中，一个意想不到的复杂层在于大量的基因，这些基因似乎不编码蛋白质，但产生各种非编码RNA。特别地，目前预测人类基因组包含5，000 - 10，000个独立的基因单位，产生长（>200个核苷酸）非编码RNA（lncRNA）。虽然有越来越多的证据表明，这些lncRNA的大部分具有细胞功能，特别是调节蛋白质编码基因的表达，但对lncRNA基因的进化起源和多样化的过程几乎一无所知。在这里，我们表明，转座因子，通过他们的能力，移动和传播的基因组中的谱系特异性的方式，以及他们的能力，引入调控序列后，染色体插入，代表了一个主要的力量塑造lncRNA库的人类，小鼠和斑马鱼。TE不仅构成了成熟lncRNA转录物的相当大的一部分，它们还富集在lncRNA基因附近，在那里它们经常有助于它们的转录调控。通过具体的例子，我们提供的证据表明，嵌入lncRNA中的一些TE序列对lncRNA的生物发生至关重要，并可能对它们的功能很重要。
Advances in vertebrate genomics have uncovered thousands of loci encoding long noncoding RNAs (lncRNAs). While progress has been made in elucidating the regulatory functions of lncRNAs, little is known about their origins and evolution. Here we explore the contribution of transposable elements (TEs) to the makeup and regulation of lncRNAs in human, mouse, and zebrafish. Surprisingly, TEs occur in more than two thirds of mature lncRNA transcripts and account for a substantial portion of total lncRNA sequence (∼30% in human), whereas they seldom occur in protein-coding transcripts. While TEs contribute less to lncRNA exons than expected, several TE families are strongly enriched in lncRNAs. There is also substantial interspecific variation in the coverage and types of TEs embedded in lncRNAs, partially reflecting differences in the TE landscapes of the genomes surveyed. In human, TE sequences in lncRNAs evolve under greater evolutionary constraint than their non–TE sequences, than their intronic TEs, or than random DNA. Consistent with functional constraint, we found that TEs contribute signals essential for the biogenesis of many lncRNAs, including ∼30,000 unique sites for transcription initiation, splicing, or polyadenylation in human. In addition, we identified ∼35,000 TEs marked as open chromatin located within 10 kb upstream of lncRNA genes. The density of these marks in one cell type correlate with elevated expression of the downstream lncRNA in the same cell type, suggesting that these TEs contribute to cis-regulation. These global trends are recapitulated in several lncRNAs with established functions. Finally a subset of TEs embedded in lncRNAs are subject to RNA editing and predicted to form secondary structures likely important for function. In conclusion, TEs are nearly ubiquitous in lncRNAs and have played an important role in the lineage-specific diversification of vertebrate lncRNA repertoires. An unexpected layer of complexity in the genomes of humans and other vertebrates lies in the abundance of genes that do not appear to encode proteins but produce a variety of non-coding RNAs. In particular, the human genome is currently predicted to contain 5,000–10,000 independent gene units generating long (>200 nucleotides) noncoding RNAs (lncRNAs). While there is growing evidence that a large fraction of these lncRNAs have cellular functions, notably to regulate protein-coding gene expression, almost nothing is known on the processes underlying the evolutionary origins and diversification of lncRNA genes. Here we show that transposable elements, through their capacity to move and spread in genomes in a lineage-specific fashion, as well as their ability to introduce regulatory sequences upon chromosomal insertion, represent a major force shaping the lncRNA repertoire of humans, mice, and zebrafish. Not only do TEs make up a substantial fraction of mature lncRNA transcripts, they are also enriched in the vicinity of lncRNA genes, where they frequently contribute to their transcriptional regulation. Through specific examples we provide evidence that some TE sequences embedded in lncRNAs are critical for the biogenesis of lncRNAs and likely important for their function.
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影响因子：
64.5
作者：
Cawley, S;Bekiranov, S;Gingeras, TR
通讯作者：
Gingeras, TR
影响因子：
64.8
作者：
Carrieri, Claudia;Cimatti, Laura;Gustincich, Stefano
通讯作者：
Gustincich, Stefano
影响因子：
4.5
作者：
de Koning AP;Gu W;Castoe TA;Batzer MA;Pollock DD
通讯作者：
Pollock DD
影响因子：
9.8
作者：
Church DM;Goodstadt L;Hillier LW;Zody MC;Goldstein S;She X;Bult CJ;Agarwala R;Cherry JL;DiCuccio M;Hlavina W;Kapustin Y;Meric P;Maglott D;Birtle Z;Marques AC;Graves T;Zhou S;Teague B;Potamousis K;Churas C;Place M;Herschleb J;Runnheim R;Forrest D;Amos-Landgraf J;Schwartz DC;Cheng Z;Lindblad-Toh K;Eichler EE;Ponting CP;Mouse Genome Sequencing Consortium
通讯作者：
Mouse Genome Sequencing Consortium
影响因子：
10.5
作者：
Cabili, Moran N.;Trapnell, Cole;Rinn, John L.
通讯作者：
Rinn, John L.