多囊卵巢综合征中 EIF2AK2 的 RNA 编辑失调：临床相关性和功能意义。

Dysregulated RNA editing of EIF2AK2 in polycystic ovary syndrome: clinical relevance and functional implications.

机构信息

Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China.

Department of Pediatrics, Affiliated Hospital of Jiangnan University, Wuxi, 214122, Jiangsu, China.

出版信息

BMC Med. 2024 Jun 10;22(1):229. doi: 10.1186/s12916-024-03434-8.

DOI:10.1186/s12916-024-03434-8

PMID:38853264

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11163819/

Abstract

BACKGROUND

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive ages. Our previous study has implicated a possible link between RNA editing and PCOS, yet the actual role of RNA editing, its association with clinical features, and the underlying mechanisms remain unclear.

METHODS

Ten RNA-Seq datasets containing 269 samples of multiple tissue types, including granulosa cells, T helper cells, placenta, oocyte, endometrial stromal cells, endometrium, and adipose tissues, were retrieved from public databases. Peripheral blood samples were collected from twelve PCOS and ten controls and subjected to RNA-Seq. Transcriptome-wide RNA-Seq data analysis was conducted to identify differential RNA editing (DRE) between PCOS and controls. The functional significance of DRE was evaluated by luciferase reporter assays and overexpression in human HEK293T cells. Dehydroepiandrosterone and lipopolysaccharide were used to stimulate human KGN granulosa cells to evaluate gene expression.

RESULTS

RNA editing dysregulations across multiple tissues were found to be associated with PCOS in public datasets. Peripheral blood transcriptome analysis revealed 798 DRE events associated with PCOS. Through weighted gene co-expression network analysis, our results revealed a set of hub DRE events in PCOS blood. A DRE event in the eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2:chr2:37,100,559) was associated with PCOS clinical features such as luteinizing hormone (LH) and the ratio of LH over follicle-stimulating hormone. Luciferase assays, overexpression, and knockout of RNA editing enzyme adenosine deaminase RNA specific (ADAR) showed that the ADAR-mediated editing cis-regulated EIF2AK2 expression. EIAF2AK2 showed a higher expression after dehydroepiandrosterone and lipopolysaccharide stimulation, triggering changes in the downstrean MAPK pathway.

CONCLUSIONS

Our study presented the first evidence of cross-tissue RNA editing dysregulation in PCOS and its clinical associations. The dysregulation of RNA editing mediated by ADAR and the disrupted target EIF2AK2 may contribute to PCOS development via the MPAK pathway, underlining such epigenetic mechanisms in the disease.

摘要

背景

多囊卵巢综合征（PCOS）是一种常见的内分泌疾病，影响育龄妇女。我们之前的研究表明 RNA 编辑与 PCOS 之间可能存在关联，但 RNA 编辑的确切作用、与临床特征的关联以及潜在机制尚不清楚。

方法

从公共数据库中检索了包含 269 个组织类型样本的十个 RNA-Seq 数据集，包括颗粒细胞、辅助性 T 细胞、胎盘、卵母细胞、子宫内膜基质细胞、子宫内膜和脂肪组织。从 12 名 PCOS 患者和 10 名对照者中采集外周血样本，并进行 RNA-Seq。通过 RNA-Seq 对 PCOS 和对照组之间的差异 RNA 编辑（DRE）进行全转录组数据分析。通过荧光素酶报告基因检测和人 HEK293T 细胞过表达评估 DRE 的功能意义。使用脱氢表雄酮和脂多糖刺激人 KGN 颗粒细胞以评估基因表达。

结果

在公共数据集，我们发现多个组织中的 RNA 编辑失调与 PCOS 相关。外周血转录组分析显示 798 个与 PCOS 相关的 DRE 事件。通过加权基因共表达网络分析，我们的研究结果揭示了 PCOS 血液中一组关键的 DRE 事件。EIF2AK2 中的一个 RNA 编辑事件（EIF2AK2：chr2:37,100,559）与 PCOS 的临床特征（如黄体生成素（LH）和 LH 与卵泡刺激素的比值）相关。荧光素酶检测、过表达和 RNA 编辑酶腺苷脱氨酶 RNA 特异性（ADAR）的敲除表明，ADAR 介导的 EIF2AK2 表达的顺式调控。EIF2AK2 在脱氢表雄酮和脂多糖刺激后表达升高，触发下游 MAPK 通路的变化。