Department of Genetic Medicine and Development, University of Geneva Medical School, 1 rue Michel-Servet, 1211 Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), 1211 Geneva, Switzerland; Institute for Information Transmission Problems (Kharkevich Institute), Russian Academy of Sciences, Moscow 127994, Russia.
Am J Hum Genet. 2013 Dec 5;93(6):1015-26. doi: 10.1016/j.ajhg.2013.10.022. Epub 2013 Nov 21.
Large intergenic noncoding RNAs (lincRNAs) are still poorly functionally characterized. We analyzed the genetic and epigenetic regulation of human lincRNA expression in the GenCord collection by using three cell types from 195 unrelated European individuals. We detected a considerable number of cis expression quantitative trait loci (cis-eQTLs) and demonstrated that the genetic regulation of lincRNA expression is independent of the regulation of neighboring protein-coding genes. lincRNAs have relatively more cis-eQTLs than do equally expressed protein-coding genes with the same exon number. lincRNA cis-eQTLs are located closer to transcription start sites (TSSs) and their effect sizes are higher than cis-eQTLs found for protein-coding genes, suggesting that lincRNA expression levels are less constrained than that of protein-coding genes. Additionally, lincRNA cis-eQTLs can influence the expression level of nearby protein-coding genes and thus could be considered as QTLs for enhancer activity. Enrichment of expressed lincRNA promoters in enhancer marks provides an additional argument for the involvement of lincRNAs in the regulation of transcription in cis. By investigating the epigenetic regulation of lincRNAs, we observed both positive and negative correlations between DNA methylation and gene expression (expression quantitative trait methylation [eQTMs]), as expected, and found that the landscapes of passive and active roles of DNA methylation in gene regulation are similar to protein-coding genes. However, lincRNA eQTMs are located closer to TSSs than are protein-coding gene eQTMs. These similarities and differences in genetic and epigenetic regulation between lincRNAs and protein-coding genes contribute to the elucidation of potential functions of lincRNAs.
长链非编码 RNA（lincRNA）的功能仍未得到充分的研究。我们通过使用来自 195 个无关欧洲个体的三种细胞类型，分析了 GenCord 集合中人类 lincRNA 表达的遗传和表观遗传调控。我们检测到相当数量的顺式表达数量性状基因座（cis-eQTL），并证明 lincRNA 表达的遗传调控与邻近蛋白质编码基因的调控是独立的。lincRNA 比具有相同外显子数的同等表达的蛋白质编码基因具有更多的顺式-eQTL。lincRNA cis-eQTL 更靠近转录起始位点（TSS），其效应大小高于蛋白质编码基因的 cis-eQTL，表明 lincRNA 表达水平的约束性小于蛋白质编码基因。此外，lincRNA cis-eQTL 可以影响附近蛋白质编码基因的表达水平，因此可以被认为是增强子活性的 QTL。表达的 lincRNA 启动子在增强子标记中的富集为 lincRNA 参与顺式转录调控提供了额外的论据。通过研究 lincRNA 的表观遗传调控，我们观察到 DNA 甲基化与基因表达之间存在正相关和负相关（表达定量性状甲基化[eQTM]），正如预期的那样，并且发现 DNA 甲基化在基因调控中的被动和主动作用的景观与蛋白质编码基因相似。然而，lincRNA eQTM 比蛋白质编码基因 eQTM 更靠近 TSS。这些 lincRNA 和蛋白质编码基因在遗传和表观遗传调控方面的相似性和差异有助于阐明 lincRNA 的潜在功能。
