Wang Bo, Ji Guanyu, Naeem Haroon, Wang Junwen, Kantharidis Phillip, Powell David, Ricardo Sharon D
Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
Shenzhen E-GENE Tech Co., Ltd., Shenzhen, China.
Front Physiol. 2018 Dec 10;9:1755. doi: 10.3389/fphys.2018.01755. eCollection 2018.
Transforming growth factor-beta (TGF-β1) plays an important regulatory role in the progression of chronic kidney failure. Further, damage to kidney glomerular mesangial cells is central to the progression of diabetic nephropathy. The aim of this study was to explore the genetic associations between mRNA, microRNA, and epigenetics in mesangial cells in response to TGF-β1. The regulatory effects of TGF-β1 on mesangial cells were investigated at different molecular levels by treating mesangial cells with TGF-β1 for 3 days followed by genome-wide miRNA, RNA, DNA methylation, and H3K27me3 expression profiling using next generation sequencing (NGS). Our results provide the first comprehensive, computationally integrated report of RNA-Seq, miRNA-Seq, and epigenomic analyses across all genetic variations, confirming the occurrence of DNA methylation and H3K27me3 in response to TGF-β1. Our findings show that the expression of KLF7 and Gja4 are involved in TGF-β1 regulated DNA methylation. Our data also provide evidence of the association between epigenetic changes and the expression of genes closely related to TGF-β1 regulation. This study has advanced our current knowledge of mechanisms that contribute to the expression of TGF-β1-regulated genes involved in the pathogenesis of kidney disease. The molecular underpinnings of TGF-β1 stimulation of kidney cells was determined, thereby providing a robust platform for further target exploration.
转化生长因子-β1（TGF-β1）在慢性肾衰竭进展中发挥重要调节作用。此外，肾小球系膜细胞损伤是糖尿病肾病进展的核心。本研究旨在探讨系膜细胞中mRNA、微小RNA和表观遗传学在响应TGF-β1时的基因关联。通过用TGF-β1处理系膜细胞3天，然后使用下一代测序（NGS）进行全基因组miRNA、RNA、DNA甲基化和H3K27me3表达谱分析，在不同分子水平上研究TGF-β1对系膜细胞的调节作用。我们的结果提供了首个全面的、通过计算整合的RNA序列、miRNA序列和表观基因组分析报告，涵盖所有基因变异，证实了响应TGF-β1时DNA甲基化和H3K27me3的发生。我们的研究结果表明，KLF7和Gja4的表达参与TGF-β1调节的DNA甲基化。我们的数据还提供了表观遗传变化与TGF-β1调节密切相关基因表达之间关联的证据。本研究推进了我们目前对导致参与肾病发病机制的TGF-β1调节基因表达的机制的认识。确定了TGF-β1刺激肾细胞的分子基础，从而为进一步的靶点探索提供了一个有力的平台。
