Palumaa Teele, Balamurugan Shruti, Pardue Machelle T
Department of Ophthalmology, Emory University, Atlanta, GA, United States.
Institute of Genomics, University of Tartu, Tartu, Estonia.
Front Med (Lausanne). 2025 Jan 14;11:1479891. doi: 10.3389/fmed.2024.1479891. eCollection 2024.
Myopia prevalence is increasing at alarming rates, yet the underlying mechanistic causes are not understood. Several studies have employed experimental animal models of myopia and transcriptome profiling to identify genes and pathways contributing to myopia. In this study, we determined the retinal transcriptome changes in response to form deprivation in mouse retinas. We then conducted a transcriptome meta-analysis incorporating all publicly available datasets and analyzed how the results related to the genes associated with refractive errors in human genome-wide association studies (GWAS).
Form deprivation was induced in three male C57BL6/J mice from postnatal day 28 (P28) to P42. Retinal gene expression was analyzed with RNA sequencing, followed by differential gene expression analysis with DESeq2 and identification of associated pathways with the Kyoto Encyclopedia of Genes and Genomes (KEGG). A systematic search identified four similar retinal transcriptomics datasets in response to experimental myopia using chicks or mice. The five studies underwent transcriptome meta-analyses to determine retinal gene expression changes and associated pathways. The results were compared with genes associated with human myopia.
Differential gene expression analysis of form-deprived mouse retinas revealed 235 significantly altered transcripts, implicating the BMP2 signaling pathway and circadian rhythms, among others. Transcriptome-wide meta-analyses of experimental myopia datasets found 427 differentially expressed genes in the mouse model and 1,110 in the chick model, with limited gene overlap between species. Pathway analysis of these two gene sets implicated TGF-beta signaling and circadian rhythm pathways in both mouse and chick retinas. Some pathways associated only with mouse retinal changes included dopamine signaling and HIF-1 signaling pathway, whereas glucagon signaling was only associated with gene changes in chick retinas. The follistatin gene changed in both mouse and chick retinas and has also been implicated in human myopia. TGF-beta signaling pathway and circadian entrainment processes were associated with myopia in mice, chicks, and humans.
This study highlights the power of combining datasets to enhance statistical power and identify robust gene expression changes across different experimental animal models and conditions. The data supports other experimental evidence that TGF-beta signaling pathway and circadian rhythms are involved in myopic eye growth.
近视患病率正以惊人的速度上升，但其潜在的机制原因尚不清楚。多项研究采用近视实验动物模型和转录组分析来确定导致近视的基因和途径。在本研究中，我们确定了小鼠视网膜对形觉剥夺的转录组变化。然后，我们进行了一项转录组荟萃分析，纳入了所有公开可用的数据集，并分析了这些结果与人类全基因组关联研究（GWAS）中与屈光不正相关基因的关系。
从出生后第28天（P28）至P42对三只雄性C57BL6/J小鼠进行形觉剥夺。用RNA测序分析视网膜基因表达，随后用DESeq2进行差异基因表达分析，并用京都基因与基因组百科全书（KEGG）鉴定相关途径。通过系统检索，确定了四个使用小鸡或小鼠的、类似的、针对实验性近视的视网膜转录组学数据集。对这五项研究进行转录组荟萃分析，以确定视网膜基因表达变化和相关途径。将结果与人类近视相关基因进行比较。
对形觉剥夺小鼠视网膜的差异基因表达分析显示，有235个转录本发生了显著变化，涉及骨形态发生蛋白2（BMP2）信号通路和昼夜节律等。对实验性近视数据集进行全转录组荟萃分析发现，小鼠模型中有427个差异表达基因，小鸡模型中有1110个，不同物种间基因重叠有限。对这两组基因的通路分析表明，转化生长因子-β（TGF-β）信号通路和昼夜节律通路在小鼠和小鸡视网膜中均有涉及。一些仅与小鼠视网膜变化相关的通路包括多巴胺信号通路和低氧诱导因子-1（HIF-1）信号通路，而胰高血糖素信号通路仅与小鸡视网膜中的基因变化相关。卵泡抑素基因在小鼠和小鸡视网膜中均发生变化，且也与人类近视有关。TGF-β信号通路和昼夜节律调节过程与小鼠、小鸡和人类的近视有关。
本研究强调了合并数据集以增强统计效力并识别不同实验动物模型和条件下稳健的基因表达变化的作用。数据支持了其他实验证据，即TGF-β信号通路和昼夜节律与近视眼的生长有关。
