Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, United States of America.
Graduate program in the Biology of Aging, University of Southern California, Los Angeles, California, United States of America.
PLoS Genet. 2024 Jun 7;20(6):e1011311. doi: 10.1371/journal.pgen.1011311. eCollection 2024 Jun.
Long interspersed element 1 (LINE-1; L1) are a family of transposons that occupy ~17% of the human genome. Though a small number of L1 copies remain capable of autonomous transposition, the overwhelming majority of copies are degenerate and immobile. Nevertheless, both mobile and immobile L1s can exert pleiotropic effects (promoting genome instability, inflammation, or cellular senescence) on their hosts, and L1's contributions to aging and aging diseases is an area of active research. However, because of the cell type-specific nature of transposon control, the catalogue of L1 regulators remains incomplete. Here, we employ an eQTL approach leveraging transcriptomic and genomic data from the GEUVADIS and 1000Genomes projects to computationally identify new candidate regulators of L1 RNA levels in lymphoblastoid cell lines. To cement the role of candidate genes in L1 regulation, we experimentally modulate the levels of top candidates in vitro, including IL16, STARD5, HSD17B12, and RNF5, and assess changes in TE family expression by Gene Set Enrichment Analysis (GSEA). Remarkably, we observe subtle but widespread upregulation of TE family expression following IL16 and STARD5 overexpression. Moreover, a short-term 24-hour exposure to recombinant human IL16 was sufficient to transiently induce subtle, but widespread, upregulation of L1 subfamilies. Finally, we find that many L1 expression-associated genetic variants are co-associated with aging traits across genome-wide association study databases. Our results expand the catalogue of genes implicated in L1 RNA control and further suggest that L1-derived RNA contributes to aging processes. Given the ever-increasing availability of paired genomic and transcriptomic data, we anticipate this new approach to be a starting point for more comprehensive computational scans for regulators of transposon RNA levels.
长散布元件 1（LINE-1；L1）是一类转座子，它们占据人类基因组的~17%。虽然一小部分 L1 拷贝仍然能够自主转座，但绝大多数拷贝已经退化且不能移动。尽管如此，移动和不移动的 L1 都可以对其宿主产生多效性影响（促进基因组不稳定、炎症或细胞衰老），L1 对衰老和衰老疾病的贡献是一个活跃的研究领域。然而，由于转座子控制的细胞类型特异性，L1 调节剂的目录仍然不完整。在这里，我们利用 GEUVADIS 和 1000Genomes 项目的转录组和基因组数据的 eQTL 方法，从计算上确定新的候选 L1 RNA 水平在淋巴母细胞系中的调节剂。为了巩固候选基因在 L1 调控中的作用，我们在体外实验调节了 top 候选基因的水平，包括 IL16、STARD5、HSD17B12 和 RNF5，并通过基因集富集分析（GSEA）评估 TE 家族表达的变化。值得注意的是，我们观察到 IL16 和 STARD5 过表达后 TE 家族表达的微妙但广泛的上调。此外，短暂的 24 小时暴露于重组人 IL16 足以短暂诱导 L1 亚家族的微妙但广泛的上调。最后，我们发现许多与 L1 表达相关的遗传变异与全基因组关联研究数据库中的衰老特征密切相关。我们的研究结果扩展了与 L1 RNA 控制相关的基因目录，并进一步表明 L1 衍生的 RNA 有助于衰老过程。鉴于基因组和转录组数据的可用性不断增加，我们预计这种新方法将成为更全面的转座子 RNA 水平调节剂计算扫描的起点。
