Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer
Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer
复制标题
DOI：
10.1038/nm1398
复制
发表时间：
2006-05-01
期刊：
影响因子：
82.9
通讯作者：
Naldini, Luigi
中科院分区：
文献类型：
--
作者：
Brown, Brian D.;Venneri, Mary Anna;Naldini, Luigi
microRNAs（miRNAs）是一类通过抑制靶细胞转录本的翻译来调控基因表达的小分子非编码RNA。越来越多的证据表明，miRNA具有独特的表达谱，并在许多细胞过程中发挥关键作用，尽管miRNA调控的程度尚不清楚。通过用编码内源性miRNAs靶序列的慢病毒载体攻击小鼠，我们显示了miRNAs在不同组织中明显分离基因表达的效率。转基因表达载体纳入目标序列的mir-142- 3 p被有效地抑制在血管内和血管外造血谱系，而表达维持在非造血细胞。这种表达谱，这是无法实现的，直到现在，使稳定的基因转移免疫功能正常的小鼠，从而克服了一个主要的障碍，成功的基因治疗。我们的研究结果提供了新的原位证据的miRNA调控，并展示了一个新的范例，在载体设计与基因工程和治疗性基因转移的应用。
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by repressing translation of target cellular transcripts. Increasing evidence indicates that miRNAs have distinct expression profiles and play crucial roles in numerous cellular processes, although the extent of miRNA regulation is not well known. By challenging mice with lentiviral vectors encoding target sequences of endogenous miRNAs, we show the efficiency of miRNAs in sharply segregating gene expression among different tissues. Transgene expression from vectors incorporating target sequences for mir-142-3p was effectively suppressed in intravascular and extravascular hematopoietic lineages, whereas expression was maintained in nonhemato-poietic cells. This expression profile, which could not be attained until now, enabled stable gene transfer in immunocompetent mice, thus overcoming a major hurdle to successful gene therapy. Our results provide novel in situ evidence of miRNA regulation and demonstrate a new paradigm in vector design with applications for genetic engineering and therapeutic gene transfer.