TGF-β-induced fibrotic stress increases G-quadruplex formation in human fibroblasts
TGF-β-induced fibrotic stress increases G-quadruplex formation in human fibroblasts
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DOI：
10.1002/1873-3468.13658
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发表时间：
2019-11-15
期刊：
影响因子：
3.5
通讯作者：
Smith, Nicole M.
中科院分区：
文献类型：
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作者：
Toshniwal, Priyanka;Nguyen, Michelle;Smith, Nicole M.
伤口愈合后的瘢痕形成是一个主要的医学问题。更好地了解伤口愈合过程中基因组的动态核结构可以深入了解潜在的病理生理学，并实现新的治疗策略。在这里，我们证明了TGF-β诱导的纤维化应力增加了皮肤成纤维细胞中称为G-四链体的动态二级DNA结构的形成，这与胶原蛋白1的表达增加一致。这种G-四链体的形成被细胞内Ca 2+内流的小分子抑制剂和抗纤维化化合物减弱。此外，我们确定了G-四链体形成序列的启动子区的COL 1A 1，它编码胶原蛋白1，并确认他们的能力，形成G-四链体结构的生理相关条件下。我们的研究结果揭示了G-四链体和瘢痕形成之间的联系，这可能导致新的治疗干预。
Scar formation after wound healing is a major medical problem. A better understanding of the dynamic nuclear architecture of the genome during wound healing could provide insights into the underlying pathophysiology and enable novel therapeutic strategies. Here, we demonstrate that TGF-beta-induced fibrotic stress increases formation of the dynamic secondary DNA structures called G-quadruplexes in skin fibroblasts, which is coincident with increased expression of collagen 1. This G-quadruplex formation is attenuated by a small molecule inhibitor of intracellular Ca2+ influx and an anti-fibrotic compound. In addition, we identify G-quadruplex-forming sequences in the promoter region of COL1A1, which encodes collagen 1, and confirm their ability to form G-quadruplex structures under physiologically relevant conditions. Our findings reveal a link between G-quadruplexes and scar formation that may lead to novel therapeutic interventions.