RNA激活

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RNA激活(RNA activation, RNAa) 是一种由小分子RNA介导的特异性基因表达上调机制,是李龙承等[1]于2006年首先在人细胞中发现并命名的。随后,其他研究小组也报道了相似的现象,证明了RNA激活是从人及大小鼠等哺乳类动物到植物及线虫中的保守现象[2][3][4][5][6][7][8][9][10]。RNA激活是由靶向基因启动子区域的双链小RNA(dsRNA)分子介导并需要Argonaute(AGO)蛋白的参与[1][11]。这类能够诱导RNA激活现象(即激活基因表达)的dsRNA被称为小激活RNA(small activating RNA,saRNA)[12]。saRNA可通过人工设计及化学合成而获得,也可为天然存在的内源性RNA如miRNA;前者介导的RNA激活被称为外源性RNA激活,后者为内源性RNA激活。

与RNA干扰(RNAi)的异同[编辑]

介导外源性RNA激活的saRNA与介导RNAi的siRNA结构相似, 是含21个核苷酸的双链RNA(dsRNA),其兩条链在各自的3’端含2个核苷酸的突出。和RNAi一样,RNAa也需要AGO蛋白特别是AGO2的参与,其作用可能是处理和活化saRNA分子,并介导saRNA与其启动子上的靶位点结合。与RNAi(主要发生在胞浆)不同的是,RNA激活机制发生在细胞核,介导RNA激活的saRNA靶向启动子而不是mRNA序列,此外,RNA激活具有特殊的时效性,表现为其效果(基因表达上调)的出现呈现48小时左右的滞后,及效果的长久性(10-14天)[1][13][14]。其机制被认为是因为RNA激活导致了表观遗传的改变[15]

内源性RNA激活[编辑]

2008年Place等[16]报道了天然存在的miRNA也能够靶向启动子序列而诱导RNA激活。他们发现人CDH1及CSDC2基因启动子存在miR-373的靶位点,在人肿瘤细胞中引入miR-373的模拟物(mimics)能激活其靶基因的表达。后来,Huang等进一步证实了内源性miRNA介导的RNAa,并且发现该机制在正常及肿瘤细胞的增殖中起重要作用[17]。Xiao等还报道了靶向增强子区域的miRNA也能够诱导RNA激活[18]。Chaluvally-Raghavan等发现miR-551b-3p通过靶向激活STAT3而促进卵巢癌细胞增殖、生存和肿瘤生长[19]。目前对于有多少基因受到内源性RNA激活机制的调控还不清楚,但有研究发现miRNA[20]及AGO蛋白[21]在人基因组的启动子区存在广泛的结合位点,提示miRNA可能在转录或者表观遗传水平调控大量的基因。

RNA激活的应用[编辑]

RNA激活是一种简单易行的上调基因表达的方法,在生物医学领域具有广泛的潜在用途,包括作为工具用于研究基因的功能[22]和对细胞进行重新编程[23][24][25][26],以及作为治疗疾病的手段,包括肿瘤、心血管疾病、勃起功能障碍等[27][28][29][30][31][32]。目前,治疗肝癌的saRNA药已经进入临床试验[28]

參考來源[编辑]

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