目的 基于高通量测序检测妊娠期高血压患者与健康产妇胎盘中环状RNA(circRNA)表达差异,探讨妊娠期高血压发病机制。方法 选取某三甲医院2018-02至2018-12期间收治的6例患有妊娠期高血压的产妇为研究对象(M组),选择同期的6例健康产妇作为对照组(C组)。采用BWA-MEM将妊娠高血压组患者与健康对照组的胎盘组织质控后测序,使用CIRI2对circRNA鉴定,并确定circRNA来源。利用DEGseq进行circRNA差异表达分析。采用miRanda软件和该物种的miRBase序列来预测circRNA的靶标miRNA,再利用Targetscan数据库预测相应的mRNA。将差异circRNA靶基因进行GO和KEGG富集分析,并导入String在线数据库进行聚类分析,寻找处于网络核心的基因。结果 两组共有31个circRNA存在差异,14个下调,17个上调,其中前5个上调circRNA分别是circRNA00809、circRNA00593、circRNA00166、circRNA00184、circRNA00028,前5个下调circRNA分别是circRNA00520、circRNA00714、circRNA02491、circRNA00841、circRNA01454。GO富集分析显示,主要富集的生物学过程为生殖过程;主要富集的细胞组分是胞外区;主要富集的分子功能是电子转移活性。KEGG通路富集中,新陈代谢方面涉及的最多。相互作用网络分析可见,NOTCH1/2处于核心位置。结论 胎盘组织中31种circRNA的差异表达与妊娠期高血压相关,其可能主要通过调节物质代谢通路发挥作用,同时NOTCH1/2等基因处于调控网络中心。
Abstract
Objective To detect the difference of circular RNA (circRNA) expression in placentas between patients with gestational hypertension and healthy women based on high-throughput sequencing, and to explore the pathogenesis of gestational hypertension. Methods Six pregnant women with gestational hypertension admitted to the First Medical Center of PLA General Hospital from February 2018 to December 2018 were selected as the research objects (group M), and six healthy pregnant women in the same period were selected as the control group (group C). Placental tissues from patients in group M and group C were sequenced after quality control using BWA-MEM, circRNAs were identified using CIRI2, and the source of circRNAs was determined. CircRNA differential expression analysis was performed using DEGseq. The target miRNA of circRNA was predicted by miRanda software and miRBase sequence of this species, and the corresponding mRNA was predicted by Targetscan database. GO and KEGG enrichment analysis were performed on the differentially expressed circRNA target genes, and the genes were imported into String online database for cluster analysis, and the genes at the core of the network were searched. Results There were 31 differential circRNAs in the two groups of samples, 14 down-regulated and 17 up-regulated, among which the first five up-regulated circRNAs were circRNA00809, circRNA00593, circRNA00166, circRNA00184 and circRNA00028 respectively, and the first five down-regulated circRNAs were circRNA00520, circRNA00714, circRNA02491, circRNA00841 and circRNA01454 respectively. GO enrichment analysis showed that the main biological process of enrichment was reproduction process. The main enriched cell component was extracellular region. The main enriched molecular function was electron transfer activity. Metabolism was the most involved in the enrichment of KEGG pathway. Interaction network analysis showed that NOTCH1/2 was at the core. Conclusions The differential expression of 31 circRNAs in placenta is associated with gestational hypertension, which may play a role by regulating metabolic pathways, and NOTCH1/2 and other genes are at the center of regulatory network.
关键词
妊娠期高血压 /
高通量测序 /
circRNA /
胎盘
Key words
gestational hypertension /
high-throughput sequencing /
circRNA /
placenta
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参考文献
[1] Lewandowska M, Więckowska B, Sajdak S, et al. Pre-Pregnancy obesity vs. other risk factors in probability models of preeclampsia and gestational hypertension[J]. Nutrients, 2020,12(9):512-522
[2] 杨清凤, 知诗卓玛, 刘继红. 子痫前期与宫内死胎的相关性研究进展[J]. 中国卫生标准管理,2022,13(1):191-195.
[3] 崔佳蕾, 王永红. 微粒调控中性粒细胞胞外诱捕网的表达在子痫前期发病中的作用研究进展[J]. 国际妇产科学杂志,2020,47(4):373-377.
[4] 冯晓玲, 郭鲁秦, 李 娜. 胎盘外泌体在子痫前期的研究进展[J]. 国际生殖健康/计划生育杂志,2020,39(4):345-348.
[5] 刘 娇, 刘国龙, 郭正晨,等. 胎盘来源microRNAs与子痫前期发病机制的研究进展[J]. 天津医药,2018,46(8):890-893.
[6] 何豆豆, 孙晓彤, 张慧芳,等.不同来源外泌体中微小RNA在子痫前期的研究进展[J]. 国际妇产科学杂志, 2022, 49(4): 426-429, 438.
[7] 周文利, 贾彦如, 王永红. miR-141的靶蛋白在子痫前期患者胎盘组织中表达的研究进展[J]. 中华临床医师杂志(电子版), 2016, 10(20):3076-3080.
[8] 王丽静, 王富荣, 孙娴莉,等. Elabela在子痫前期中的研究进展[J]. 国际妇产科学杂志,2022,49(2):121-124.
[9] Johnson S J, Cooper T A. Overlapping mechanisms of lncRNA and expanded microsatellite RNA[J]. Wiley Interdiscip Rev RNA, 2021,12(1):e1634.
[10] Hansen T B, Jensen T I, Clausen B H, et al. Natural RNA circles function as efficient microRNA sponges[J]. Nature, 2013, 495 (7441): 384-388.
[11] Memczak S, Jens M, Elefsinioti A, et al. Circular RNAs are a large class of animal RNAs with regulatory potency[J]. Nature, 2013,495(7441):333-338.
[12] 李 琦, 田江天, 田进伟,等. 环状RNA的功能以及调控动脉粥样硬化发生发展的研究进展[J]. 中国病理生理杂志, 2019, 35(11): 2103-2107, 2112.
[13] 宗曾艳, 孔凡虹, 王萌萌,等. 环状RNA在恶性肿瘤发生发展和诊疗中的研究进展[J]. 国际检验医学杂志, 2020, 41(1):98-103.
[14] 张雪颖, 应小燕, 许波群. 环状RNA在女性生殖系统中的研究进展[J]. 国际生殖健康/计划生育杂志, 2020, 39(4):308-313.
[15] 李珍瑾, 周赛君, 郭建超. 环状RNA功能及其在糖尿病和糖尿病并发症发生发展中的作用研究进展[J]. 山东医药, 2021, 61(21):101-105.
[16] 曾奇虎, 翁静飞, 李小林,等. 环状RNA的研究进展[J]. 海南医学,2019,30(18):2427-2430.
[17] Deng N, Lei D, Huang J, et al. Circular RNA expression profiling identifies hsa_circ_0011460 as a novel molecule in severe preeclampsia[J]. Pregnancy Hypertens, 2019,17(5):216-225.
[18] Jiang M, Lash G E, Zhao X, et al. CircRNA-0004904, CircRNA-0001855, and PAPP-A: potential novel biomarkers for the prediction of preeclampsia[J]. Cell Physiol Biochem, 2018,46(6):2576-2586.
[19] Zhu H, Niu X, Li Q, et al. Circ_0085296 suppresses trophoblast cell proliferation, invasion, and migration via modulating miR-144/E-cadherin axis[J]. Placenta, 2020,97(1):18-25.
[20] Zhang C, Hu J, Yu Y. CircRNA is a rising star in researches of ocular diseases[J]. Front Cell Dev Biol, 2020,8(2):850-861.
[21] Prameswari N, Irwinda R, Wibowo N, et al. Maternal amino acid status in severe preeclampsia: a cross-sectional study[J]. Nutrients, 2022,14(5):501-509.
[22] Moraes J, Behura S K, Geary T W, et al. Analysis of the uterine lumen in fertility-classified heifers: I. Glucose, prostaglandins, and lipids?[J]. Biol Reprod, 2020,102(2):456-474.
[23] Gardner D K. Lactate production by the mammalian blastocyst: manipulating the microenvironment for uterine implantation and invasion?[J]. Bioessays, 2015,37(4):364-371.
[24] Frolova A I, O’Neill K, Moley K H. Dehydroepiandrosterone inhibits glucose flux through the pentose phosphate pathway in human and mouse endometrial stromal cells, preventing decidualization and implantation[J]. Mol Endocrinol, 2011,25(8):1444-1455.
[25] Hirschmugl B, Perazzolo S, Sengers B G, et al. Placental mobilization of free fatty acids contributes to altered materno-fetal transfer in obesity[J]. Int J Obes (Lond), 2021,21(4):378-389.
[26] Uken K L, Schäff C T, Vogel L, et al. Modulation of colostrum composition and fatty acid status in neonatal calves by maternal supplementation with essential fatty acids and conjugated linoleic acid starting in late lactation[J]. J Dairy Sci, 2021,14(5):128-136.
[27] Ou Y, Zhu L, Wei X, et al. Circular RNA circ_0111277 attenuates human trophoblast cell invasion and migration by regulating miR-494/HTRA1/Notch-1 signal pathway in pre-eclampsia[J]. Cell Death Dis, 2020,11(6):479-490.
[28] Vanaroj P, Chaijaroenkul W, Na-Bangchang K. Notch signaling in the pathogenesis, progression and identification of potential targets for cholangiocarcinoma (Review)[J]. Mol Clin Oncol, 2022,16(3):66-74.
[29] Hamada Y, Hiroe T, Suzuki Y, et al. Notch2 is required for formation of the placental circulatory system, but not for cell-type specification in the developing mouse placenta[J]. Differentiation, 2007,75(3):268-278.
[30] Liu J J, Zhang L, Zhang F F, et al. Influence of miR-34a on preeclampsia through the Notch signaling pathway[J]. Eur Rev Med Pharmacol Sci, 2019,23(3):923-931.
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