Identification of human mitochondrial RNA cleavage sites and candidate RNA processing factors.
Identification of human mitochondrial RNA cleavage sites and candidate RNA processing factors.
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DOI：
10.1186/s12915-022-01373-5
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发表时间：
2022-07-22
期刊：
影响因子：
5.4
通讯作者：
Hodgkinson, Alan
中科院分区：
文献类型：
--
作者：
Carbajosa, Guillermo;Ali, Aminah T.;Hodgkinson, Alan
人类线粒体基因组被转录为含有多个基因的长链RNA，其需要转录后切割和加工以释放在细胞能量产生中起重要作用的功能性基因产物。尽管在癌症、心血管疾病和糖尿病等病理学中涉及线粒体转录后过程的知识，但人们对它们的功能在人群水平上的变化方式以及是什么驱动这些过程的变化最终影响疾病风险知之甚少。在这里，我们开发了一种从标准RNA测序数据中检测和定量线粒体RNA切割事件的方法，并将这种方法应用于来自独立队列的> 1000个样本的人类全血数据。我们检测到54个推定的线粒体RNA切割位点，不仅映射到已知的基因边界，短RNA末端和RNA修饰位点，而且还发生在内部基因位置，这表明新的线粒体RNA切割接头。推测的RNA切割速率与个体间的RNA编码基因表达相关，表明对下游过程的影响。此外，通过比较推断的切割速率与核遗传变异和基因表达，我们暗示多个基因在调节线粒体RNA切割（例如MRPP 3，TBRG 4和FASTKD 5），包括RPS 19在影响切割速率的一个潜在的新的作用，在一个网站附近的MTATP 6-COX 3连接，我们验证使用shRNA敲低数据。我们确定了与线粒体RNA加工相关的新的切割接头，以及新涉及这些过程的基因，并检测切割速率变化对下游表型和疾病过程的潜在影响。这些结果突出了线粒体转录组的复杂性，并指出了核编码基因可能影响关键线粒体过程的新机制。在线版本包含补充材料，可通过10.1186/s12915-022-01373-5获得。
The human mitochondrial genome is transcribed as long strands of RNA containing multiple genes, which require post-transcriptional cleavage and processing to release functional gene products that play vital roles in cellular energy production. Despite knowledge implicating mitochondrial post-transcriptional processes in pathologies such as cancer, cardiovascular disease and diabetes, very little is known about the way their function varies on a human population level and what drives changes in these processes to ultimately influence disease risk. Here, we develop a method to detect and quantify mitochondrial RNA cleavage events from standard RNA sequencing data and apply this approach to human whole blood data from > 1000 samples across independent cohorts. We detect 54 putative mitochondrial RNA cleavage sites that not only map to known gene boundaries, short RNA ends and RNA modification sites, but also occur at internal gene positions, suggesting novel mitochondrial RNA cleavage junctions. Inferred RNA cleavage rates correlate with mitochondrial-encoded gene expression across individuals, suggesting an impact on downstream processes. Furthermore, by comparing inferred cleavage rates to nuclear genetic variation and gene expression, we implicate multiple genes in modulating mitochondrial RNA cleavage (e.g. MRPP3, TBRG4 and FASTKD5), including a potentially novel role for RPS19 in influencing cleavage rates at a site near to the MTATP6-COX3 junction that we validate using shRNA knock down data. We identify novel cleavage junctions associated with mitochondrial RNA processing, as well as genes newly implicated in these processes, and detect the potential impact of variation in cleavage rates on downstream phenotypes and disease processes. These results highlight the complexity of the mitochondrial transcriptome and point to novel mechanisms through which nuclear-encoded genes can potentially influence key mitochondrial processes. The online version contains supplementary material available at 10.1186/s12915-022-01373-5.
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