首页> 外文期刊>Scientific reports. >microRNA-29b mediates fibrotic induction of human xylosyltransferase-I in human dermal fibroblasts via the Sp1 pathway
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microRNA-29b mediates fibrotic induction of human xylosyltransferase-I in human dermal fibroblasts via the Sp1 pathway

机译:microRNA-29b通过Sp1途径介导人皮肤成纤维细胞中人木糖基转移酶-I的纤维化诱导

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Diminished microRNA-29b levels have recently been revealed to provoke increased expression and accumulation of extracellular matrix molecules, such as collagens in fibrotic remodeling. Subsequently, the aim of this study was to find out whether microRNA-29b might also regulate human xylosyltransferase (XT)-I expression. XT-I has been characterized previously as a fibrosis biomarker catalyzing the key step of proteoglycan biosynthesis. While we demonstrate that XYLT1 is neither a target of microRNA-29b identified in silico nor a direct 3′ untranslated region binding partner of microRNA-29b, transfection of normal human dermal fibroblasts with microRNA-29b inhibitor strongly increased XYLT1 mRNA expression and XT activity. Combined results of the target prediction analysis and additional transfection experiments pointed out that microRNA-29b exerts indirect influence on XT-I by targeting the transcription factor specificity protein 1 (Sp1). We could confirm our hypothesis due to the decrease in XYLT1 promoter activity after Sp1 binding site mutation and the approval of occupancy of these binding sites by Sp1 in vitro. Taken together, a hitherto unidentified pathway of XT-I regulation via microRNA-29b/Sp1 was determined in this study. Our observations will facilitate the understanding of complex molecular fibrotic pathways and provide new opportunities to investigate microRNA-based antifibrotic tools.
机译:最近发现减少的microRNA-29b水平会引起纤维化重塑中细胞外基质分子(例如胶原蛋白)的表达和积累增加。随后,这项研究的目的是找出microRNA-29b是否也可能调节人木糖基转移酶(XT)-I的表达。 XT-1先前已被表征为催化蛋白聚糖生物合成关键步骤的纤维化生物标志物。虽然我们证明XYLT1既不是在计算机中鉴定的microRNA-29b的靶标,也不是microRNA-29b的直接3'非翻译区结合伴侣,但用microRNA-29b抑制剂转染正常人皮肤成纤维细胞会大大提高XYLT1 mRNA的表达和XT活性。目标预测分析和其他转染实验的综合结果指出,microRNA-29b通过靶向转录因子特异性蛋白1(Sp1)对XT-1产生间接影响。我们可以证实我们的假设是由于Sp1结合位点突变后XYLT1启动子活性的降低以及Sp1在体外对这些结合位点的占用的批准。两者合计,在这项研究中确定了迄今为止尚未确定的通过microRNA-29b / Sp1进行XT-I调控的途径。我们的观察结果将有助于理解复杂的分子纤维化途径,并为研究基于microRNA的抗纤维化工具提供新的机会。

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