Combined analysis and verification of differential gene transcriptome and Gene Expression Omnibus database in peripheral blood of patients with proliferative diabetic retinopathy_Chinese Journal of Ocular Fundus Diseases

Authors：

Hong Yaru , Yao Xuyang , Li Hui , Cao Jingjing , Bai Xiaomei , An Weiting , Xu Zhao , Dong Lijie , Li Xiaorong ,  Liu Juping

Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China;

Corresponding author：

Liu Juping, Email: tydljp@126.com

Keywords：

Diabetic retinopathy; Transcriptome; Differential genes

DOI：

10.3760/cma.j.cn511434-20210119-00031

Video：

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Objective To screening differentially expressed genes (DEGs) in proliferative diabetic retinopathy (DR) patients to provide new biological therapeutic targets for proliferative DR (PDR) therapy. Methods A basic research. A total of 3 PDR patients (group PDR) and 3 non-diabetic patients (control group) were enrolled in the study in Tianjin Medical University Eye Hospital in October 2020. In addition, 40 cases of PDR and non-diabetic patients were selected and divided into PDR validation group and control validation group. Peripheral blood validation test was performed in PDR validation group and control validation group; RNA sequencing was performed in PDR group and control group. Transcriptomics (RNAseq) sequencing technology was used to screen DEG in PDR group and control group. The selected DEGs were analyzed by gene ontology (GO) function enrichment analysis, signal pathway enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction network (PPI). The gene expression database was used to find the high-throughput data related to PDR, and multi queue comparison analysis was carried out. The target genes of differentially expressed miRNAs were predicted through targetscan platform, so as to clearly screen the correlation between DEG and PDR. Reverse transcription polymerase chain reaction and Western blot were used to verify the expression of DEG mRNA and protein related to PDR. The relative expression of PDR related DEG mRNA and protein between PDR validation group and control validation group were compared by paired t-test. Results A total of 1 337 DEGs were screened by RNAseq sequencing in the peripheral blood of patients with PDR, of which 419 genes were up-regulated and 918 down-regulated. Among them, direct inhibitor of apoptosis protein-binding protein with low isoelectric point (DIABLO), zinc finger and BTB domain containing 10 (ZBTB10), polo-like kinases 3 (PLK3), regulatory subunit 1 (PIK3R1) and B cell translocation gene 3 (BTG3) were differentially expressed in PDR patients. The function of GO was enriched from the analysis of molecular function, biological process and cellular composition. The results showed that DIABLO, ZBTB10, PLK3, PIK3R1, BTG3 were involved in the pathological process related to PDR. KEGG enrichment analysis showed that glucose metabolic pathways such as extracellular matrix receptors, cytokine regulatory pathway, p53 signal pathway and galactose metabolism may be involved in the process of differential genes. The analysis of PPI protein interaction network showed that the larger the DEG-associated protein node, the greater the number of associated nodes. Among them, DIABLO, ZBTB10, PLK3, PIK3R1 and BTG3 played significant roles in the formation of the action network. By comparing and analyzing the existing high-throughput data related to diabetic retinopathy in Gene Expression Omnibus database and predicting by Targetscan platform, it was found that some significant differences in miRNA reported in aqueous humor, vitreous fluid and plasma of DR patients can be regulated by the differential genes found in this study. Compared with the control verification group, the relative expressions of DIABLO, ZBTB10, PLK3, PIK3R1 mRNA and protein in peripheral blood of the PDR verification group were up-regulated, and the relative expression of BTG3 mRNA and protein was down-regulated. Conclusion DIABLO, ZBTB10, PLK3, PIK3R1 and BTG3 are DEGs in patients with PDR, and they can participate in the disease process by regulating the biological processes of cell proliferation, fibrosis and oxidative stress.

Citation： Hong Yaru, Yao Xuyang, Li Hui, Cao Jingjing, Bai Xiaomei, An Weiting, Xu Zhao, Dong Lijie, Li Xiaorong, Liu Juping. Combined analysis and verification of differential gene transcriptome and Gene Expression Omnibus database in peripheral blood of patients with proliferative diabetic retinopathy. Chinese Journal of Ocular Fundus Diseases, 2022, 38(3): 225-234. doi: 10.3760/cma.j.cn511434-20210119-00031 Copy

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1. Hendrick AM, Gibson MV, Kulshreshtha A. Diabetic retinopathy[J]. Prim Care, 2015, 42(3): 451-464. DOI: 10.1016/j.pop.2015.05.005.
2. 胡志翔, 林海双, 叶凌颖, 等. 玻璃体切除术联合和非联合白内障手术治疗合并白内障的增殖期糖尿病性视网膜病变[J]. 温州医科大学学报, 2020, 50(10): 825-829. DOI: 10.3969/j.issn.2095-9400.2020.10.010.Hu ZX, Lin HS, Ye LY, et al. Vitrectomy combined with or without combined cataract surgery in the treatment of proliferative diabetic retinopathy with cataract[J]. Journal of Wenzhou Medical University, 2020, 50(10): 825-829. DOI: 10.3969/j.issn.2095-9400.2020.10.010.
3. Rodríguez-García A, Sola-Landa A, Barreiro C. RNA-seq-based comparative transcriptomics. RNA preparation and bioinformatics[J]. Methods Mol Biol, 2017, 1645: 59-72. DOI: 10.1007/978-1-4939-7183-1_5.
4. Koch CM, Chiu SF, Akbarpour M, et al. A beginner's guide to analysis of RNA sequencing data[J]. Am J Respir Cell Mol Biol, 2018, 59(2): 145-157. DOI: 10.1165/rcmb.2017-0430TR.
5. Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive for functional genomics data sets-update[J]. Nucleic Acids Res, 2013, 41: D991-995. DOI: 10.1093/nar/gks1193.
6. Gan TQ, Chen WJ, Qin H, et al. Clinical value and prospective pathway signaling of microRNA-375 in lung adenocarcinoma. A study based on the cancer genome atlas (TCGA), gene expression omnibus (GEO) and bioinformatics analysis[J]. Med Sci Monit, 2017, 23: 2453-2464. DOI: 10.12659/msm.901460.
7. Gao L, Zhang LJ, Li SH, et al. Role of miR-452-5p in the tumorigenesis of prostate cancer. A study based on the Cancer Genome Atl (TCGA), Gene Expression Omnibus (GEO), and bioinformatics analysis[J]. Pathol Res Pract, 2018, 214(5): 732-749. DOI: 10.1016/j.prp.2018.03.002.
8. Li Y, Gu J, Xu F, et al. Transcriptomic and functional network features of lung squamous cell carcinoma through integrative analysis of GEO and TCGA data[J/OL]. Sci Rep, 2018, 8(1): 15834[2018-10-26]. https://pubmed.ncbi.nlm.nih.gov/30367091/. DOI: 10.1038/s41598-018-34160-w.
9. 中华医学会眼科学会眼底病学组. 糖尿病视网膜病变分期标准[J]. 中华眼科杂志, 1985, 21(2): 113.Fundus Diseases Group of the Chinese Academy of Ophthalmology. Diabetic retinopathy staging criteria[J]. Chin J Ophthalmol, 1985, 21(2): 113.
10. 赵昔良, 叶益聪, 张抒扬. 美国糖尿病学会新版糖尿病诊断标准对择期冠状动脉造影患者糖代谢异常的筛查意义[J]. 中华内科杂志, 2015, 54(4): 302-306. DOI: 10.3760/cma.j.issn.0578-1426.2015.04.006.Zhao XL, Ye YC, Zhang SY. The values of the new American Diabetes Association diagnostic criteria for screening of pre-diabetes and diabetes in patients undergoing elective coronary angiography[J]. Chin J Intern Med, 2015, 54(4): 302-306. DOI: 10.3760/cma.j.issn.0578-1426.2015.04.006.
11. 包继文, 李子扬, 尧欢珍, 等. METTL10表达下调与足细胞损伤的关系[J]. 上海交通大学学报医学版, 2021, 41(10): 1290-1296. DOI: 10.3969/j.issn.1674-8115.2021.10.003.Bao JW, Li ZY, Yao HZ, et al. Relationship between down-regulation of METTL10 expression and podocyte injury[J]. Journal of Shanghai Jiaotong University (Medical Science), 2021, 41(10): 1290-1296. DOI: 10.3969/j.issn.1674-8115.2021.10.003.
12. Smit-McBride Z, Nguyen AT, Yu AK, et al. Unique molecular signatures of microRNAs in ocular fluids and plasma in diabetic retinopathy[J/OL]. PLoS One, 2020, 15(7): e0235541[2020-07-21]. https://pubmed.ncbi.nlm.nih.gov/32692745/. DOI: 10.1371/journal.pone.0235541.
13. Niu R, Nie ZT, Liu L, et al. Follistatin-like protein 1 functions as a potential target of gene therapy in proliferative diabetic retinopathy[J]. Aging (Albany NY), 2021, 13(6): 8643-8664. DOI: 10.18632/aging.202678.
14. 步绍翀, 张哲, 王琼, 等. 结缔组织生长因子刺激后视网膜Müller细胞基因表达谱的转录组学分析及验证[J]. 中华眼底病杂志, 2020, 36(12): 964-970. DOI: 10.3760/cma.j.cn511434-20200116-00026.Bu SC, Zhang Z, Wang Q, et al. Transcriptomic analysis and verification of gene expression profile of retinal Müller cells stimulated by connective tissue growth factor[J]. Chin J Ocul Fundus Dis, 2020, 36(12): 36(12): 964-970. DOI: 10.3760/cma.j.cn511434-20200116-00026.
15. Lazzara F, Fidilio A, Platania CBM, et al. Aflibercept regulates retinal inflammation elicited by high glucose via the PlGF/ERK pathway[J]. Biochem Pharmacol, 2019, 168: 341-351. DOI: 10.1016/j.bcp.2019.07.021.
16. Wang L, Zhou X, Yin Y, et al. Hyperglycemia induces neutrophil extracellular traps formation through an NADPH oxidase-dependent pathway in diabetic retinopathy[J/OL]. Front Immunol, 2019, 9: 3076[2019-01-08]. https://pubmed.ncbi.nlm.nih.gov/30671057/. DOI: 10.3389/fimmu.2018.03076.
17. Thapa R, Bajimaya S, Sharma S, et al. Systemic association of newly diagnosed proliferative diabetic retinopathy among type 2 diabetes patients presented at a tertiary eye hospital of Nepal[J]. Nepal J Ophthalmol, 2015, 7(1): 26-32. DOI: 10.3126/nepjoph.v7i1.13163.
18. Dong L, Lin T, Li W, et al. Antioxidative effects of polypyrimidine tract-binding protein-associated splicing factor against pathological retinal angiogenesis through promotion of mitochondrial function[J]. J Mol Med (Berl), 2021, 99(7): 967-980. DOI: 10.1007/s00109-021-02069-z.
19. 黄亮瑜, 柯屹峰, 林婷婷, 等. 慢病毒介导聚嘧啶束结合蛋白相关剪接因子对氧诱导视网膜病变小鼠视网膜新生血管的抑制作用[J]. 中华眼底病杂志, 2020, 36(1): 53-59. DOI: 10.3760/cma.j.issn.1005-1015.2020.01.012.Huang LY, Ke YF, Lin TT, et al. Inhibition of lentivirus mediated polypyrimidine binding protein related splicing factor on retinal neovascularization in mice with oxygen induced retinopathy[J]. Chin J Ocul Fundus Dis, 2020, 36(1): 53-59. DOI: 10.3760/cma.j.issn.1005-1015.2020.01.012.
20. 邢小丽, 黄亮瑜, 张哲, 等. 丁基苯酞对H2O2诱导下视网膜色素上皮细胞凋亡的保护作用[J]. 中华眼底病杂志, 2019, 35(5): 480-487. DOI: 10.3760/cma.j.issn.1005-1015.2019.05.011.Xing XL, Huang LY, Zhang Z, et al. Effects of butylphthalide on hydrogen peroxide induced retinal pigment epithelial cells injury[J]. Chin J Ocul Fundus Dis, 2019, 35(5): 480-487. DOI: 10.3760/cma.j.issn.1005-1015.2019.05.011.
21. Xing X, Huang L, Lv Y, et al. DL-3-n-butylphthalide protected retinal Müller cells dysfunction from oxidative stress[J]. Curr Eye Res, 2019, 44(10): 1112-1120. DOI: 10.1080/02713683.2019.1624777.
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Chinese Journal of Ocular Fundus Diseases

Combined analysis and verification of differential gene transcriptome and Gene Expression Omnibus database in peripheral blood of patients with proliferative diabetic retinopathy

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