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ENGLISH ABSTRACT
MeCP2诱导的视网膜色素上皮细胞转录组和m6A的改变
张咏雅
李晓华
赵雪茹
李雪
作者及单位信息
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DOI： 10.3760/cma.j.cn115989-20230920-00105
MeCP2-induced alterations of transcriptome and m6A modification in retinal pigment epithelial cell
Zhang Yongya
Li Xiaohua
Zhao Xueru
Li Xue
Authors Info & Affiliations
Zhang Yongya
Department of Ophthalmology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan Eye Hospital, Henan Key Laboratory of Ophthalmology and Visual Science, Henan Academy of Innovations in Medical Science, Zhengzhou 450003, China
Li Xiaohua
Department of Ophthalmology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan Eye Hospital, Henan Key Laboratory of Ophthalmology and Visual Science, Henan Academy of Innovations in Medical Science, Zhengzhou 450003, China
Zhao Xueru
Department of Ophthalmology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan Eye Hospital, Henan Key Laboratory of Ophthalmology and Visual Science, Henan Academy of Innovations in Medical Science, Zhengzhou 450003, China
Li Xue
Department of Ophthalmology, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan Eye Hospital, Henan Key Laboratory of Ophthalmology and Visual Science, Henan Academy of Innovations in Medical Science, Zhengzhou 450003, China
·
DOI： 10.3760/cma.j.cn115989-20230920-00105
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摘要

目的探讨重组人甲基CpG结合蛋白2(MeCP2)处理的视网膜色素上皮(RPE)细胞中mRNA和N6-甲基腺嘌呤(m6A)改变及其机制。

方法将传代ARPE-19细胞贴壁培养后分为正常对照组和MeCP2组，正常对照组细胞采用正常培养液培养，MeCP2组细胞于含终质量浓度20 ng/ml重组人MeCP2蛋白培养液中，连续培养72 h。提取细胞内总RNA进行转录组测序(RNA-seq)和甲基化免疫共沉淀测序(MeRIP-seq)分析。采用edgeR软件包根据 P<0.05筛选差异表达基因(DEGs)和差异甲基化基因(DMGs)。采用基因本体论(GO)富集分析对差异基因进行生物学功能描述，采用京都基因和基因组百科全书(KEGG)进行通路富集分析。筛选出DEGs与DMGs交集的基因，采用实时荧光定量PCR技术检测各组差异基因mRNA表达水平。

结果共筛选出DEGs 100个，DMGs 7 441个，富集分析发现DEGs与细胞外基质(ECM)－受体相互作用、细胞分裂、细胞周期和磷脂酰肌醇3激酶/蛋白激酶B(PI3K/AKT)信号通路等相关，DMGs与微管细胞骨架、血管生成、表皮生长因子受体(ErbB)信号通路、晚期糖基化终末产物(AGEs)－糖基化终末产物受体(RAGE)信号通路、哺乳动物雷帕霉素靶蛋白(mTOR)信号通路、Notch信号通路和转化生长因子β(TGF-β)信号通路等相关。DEGs中24个基因表达增加，76个基因表达减少；DMGs中5个基因含有高甲基化峰，7 439个基因含有低甲基化峰，注释峰后，正常对照组有7 626个基因发生m6A甲基化，MeCP2组有8 006个基因发生m6A甲基化，2个组间有7 360个交集基因。正常对照组和MeCP2组的m6A甲基化富集于转录本的CDS、内含子和3'-非翻译区(3'UTR)区域，其甲基化比例分别为23.62%/22.27%、48.53%/48.35%和23.66%/25.28%。联合分析发现2个上皮－间充质转化(EMT)相关基因 CSPG5和 RBP1的mRNA和m6A水平均降低。荧光定量PCR结果显示，MeCP2组 GSPG5、 RBP1、 ZNF484 mRNA相对表达量均明显低于正常对照组，差异均有统计学意义( t＝7.885、7.613、7.345，均 P<0.01)。

结论RPE细胞中MeCP2对EMT的调控机制与m6A甲基化修饰相关。 CSPG5和 RBP1基因可能是m6A甲基化的靶基因，参与MeCP2调控的EMT过程。

增生性玻璃体视网膜病变;视网膜色素上皮细胞;MeCP2;m6A;MeRIP-seq;上皮－间充质转化
ABSTRACT

ObjectiveTo investigate mRNA and N6-methyladenosine (m6A) changes in retinal pigment epithelium (RPE) cells treated with recombinant human methyl-CpG binding protein 2 (MeCP2) and the mechanisms.

MethodsThe passaged ARPE-19 cells were divided into normal control and MeCP2 groups after adhesion culture.Cells in the normal control group were continuously cultured in normal culture medium, and the cells in the MeCP2 group were cultured in culture medium containing a final concentration of 20 ng/ml of recombinant human MeCP2 protein for 72 hours.Transcriptomic sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (MeRIP-seq) were used to extract and analyze total RNA.Differentially methylated genes (DMGs) and differentially expressed genes (DEGs) were screened using the edgeR software package based on P<0.05.The biological function of differential genes was determined by gene ontology (GO) enrichment analysis, and the pathway enrichment analysis was performed by Kyoto Encyclopedia of Genes and Genomes (KEGG).Intersection of genes between DEGs and DMGs were screened, and real-time fluorescence quantitative PCR was used to determine the mRNA expression levels of differential genes.

ResultsA total of 100 DEGs and 7 441 DMGs genes were screened.According to enrichment analysis, the DEGs were enriched to extracellular matrix (ECM)-receptor interaction, cell division, phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway and so on.The DMGs were associated with microtubule cytoskeleton, angiogenesis, epidermal growth factor receptor (ErbB) signaling pathway, advanced glycation end-products (AGEs) -glycation end-products receptor (RAGE) signaling pathway, mammalian target of rapamycin (mTOR) signaling pathway, Notch signaling pathway and transforming growth factors-β (TGF-β) signaling pathway and so on.There were 24 up-regulated and 76 down-regulated DEGs.Five DMGs had hypermethylation peaks, and 7 439 DMGs had hypomethylation peaks.After annotation of peaks, 7 626 genes in the normal control group and 8 006 genes in the MeCP2 group had m6A methylation, with 7 360 intersecting genes between the two groups.The m6A methylation in the normal control group and MeCP2 group was concentrated in the CDS, intron and 3'-untranslated region (3'UTR) regions of the transcript, with the methylation ratio of 23.62%/22.27%, 48.53%/48.35% and 23.66%/25.28%, respectively.Joint analysis showed that CSPG5 and RBP1 genes related to the epithelial-mesenchymal transition (EMT) had lower amount of mRNA and m6A.Fluorescence quantitative PCR results showed that the relative mRNA expression levels of GSPG5, RBP1 and ZNF484 in MeCP2 group were significantly lower than those in normal control group ( t=7.885, 7.613, 7.345; all at P<0.01).

ConclusionsThe regulatory mechanism of MeCP2 on EMT in RPE cells is related to m6A methylation modification. CSPG5 and RBP1 genes may be the target genes of m6A methylation and participate in the EMT regulated by MeCP2.

Proliferative vitreoretinopathy;Retinal pigment epithelial cells;MeCP2;m6A;MeRIP-seq;Epithelial-mesenchymal transition
Li Xiaohua, Email: mocdef.3ab616116_lhx
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引用本文

张咏雅,李晓华,赵雪茹,等. MeCP2诱导的视网膜色素上皮细胞转录组和m6A的改变[J]. 中华实验眼科杂志,2024,42(05)：408-416.

DOI:10.3760/cma.j.cn115989-20230920-00105

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增生性玻璃体视网膜病变(proliferative vitreoretinopathy，PVR)是复发性视网膜脱离的重要原因，发病机制复杂，病理变化多样 [ 1 ]。目前，玻璃体切割术是PVR的主要治疗方法，但术后仍有复发的可能。PVR的病理特征是细胞增殖并迁移到玻璃体，以及广泛的胶质增生。在与PVR相关的视网膜前膜中已鉴定出多种细胞类型，如视网膜色素上皮(retinal pigment epithelium，RPE)细胞、成纤维细胞、肌成纤维细胞、神经胶质细胞和巨噬细胞。RPE细胞的上皮－间充质转化(epithelial-mesenchymal transition，EMT)过程被认为是PVR发展的关键步骤之一 [ 2 , 3 , 4 , 5 ]。甲基CpG结合蛋白2(methyl-CpG binding proteins 2，MeCP2)是一种甲基化的DNA结合蛋白，研究发现其异常表达与EMT、纤维化等多种病理状况有关 [ 6 , 7 , 8 , 9 ]。本课题组之前的研究发现，α-平滑肌肌动蛋白(α-smooth muscle actin，α-SMA)和P-MeCP2-421在人PVR膜上均高表达和双标记；在RPE细胞中敲减MeCP2会抑制转化生长因子β(transforming growth factor-β，TGF-β)诱导的Smad2/3激活、Ⅰ型胶原和纤维连接蛋白(fibronectin，FN)的表达，表明MeCP2在介导RPE细胞EMT/纤维化中发挥关键作用 [ 10 ]。N6-甲基腺嘌呤(N6-methyladenosine，m6A)是常见的mRNA内部化学修饰，有研究发现肿瘤细胞EMT过程中，关键转录因子Snail发生m6A修饰 [ 11 ]。越来越多的研究表明，m6A甲基化修饰参与多种生物过程，如细胞增殖、血管生成、纤维化和炎症反应等 [ 12 , 13 , 14 , 15 ]。本课题组前期采用m6A甲基化免疫共沉淀测序(methylated RNA immunoprecipitation sequencing，MeRIP-seq)和转录组测序(RNA sequencing，RNA-seq)分析TGF-β2处理RPE的差异甲基化基因(differentially methylated genes，DMGs)和差异表达基因(differentially expressed genes，DEGs)，进一步的关联分析确定12个差异基因与EMT相关 [ 16 ]。我们前期通过形态学实验发现重组蛋白MeCP2处理RPE细胞后细胞形态转变为纺锤形或不规则三角形，具有间质细胞特征。但在RPE细胞中m6A修饰与MeCP2的关系尚不完全清楚。本研究采用RNA-seq和MeRIP-seq技术分析MeCP2对RPE细胞mRNA表达和m6A修饰的影响，并探讨m6A甲基化在MeCP2调控RPE细胞EMT中的机制。
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李晓华，Email： mocdef.3ab616116_lhx
B

张咏雅：起草文章、实施研究、采集数据、统计分析、分析/解释数据；李晓华：设计实验、获取研究经费、指导实验、文章审阅、修改及定稿；赵雪茹、李雪：实施研究、采集数据、统计分析

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国家自然科学基金面上项目 (81770952)
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