生物谷报道:德克萨斯大学西南医学中心(UT Southwestern Medical Center)的研究人员最近发现了一种利用RNA改变基因活性的新途径,为治疗疾病和研究基因作用提供了新工具。具体内容刊登于《Nature Chemical Biology》。
围绕染色体DNA的蛋白混合物存在精微平衡,控制基因的表达。Bethany Janowski教授利用RNA动摇这种平衡,激活培养细胞内特定基因。文章高级作者、药理学教授David Corey博士认为,这项研究的重要意义在于能够确定诱哄基因进行表达的时间。
基因是定居于染色体上的DNA片段,携带编码蛋白的指令,基因突变导致蛋白缺失、错误表达或者表达过量,这些都可能导致疾病。围绕染色体的一团蛋白,帮助细胞确定那些基因进入转录阶段。UT Southwestern小组使用的RNA,与乳腺癌细胞特异基因的DNA片段互补。将此RNA注入这些蛋白混合物,特定基因被激活,导致癌细胞生长速率下降。Corey博士认为,新途径的激活效果发生在染色体水平,而非信使RNA水平,尽管注入的RNA链是人造的,但此RNA与染色体相互作用的过程与肌体内的天然过程相似。具体机制尚待进一步分析。
Corey和Janowski如今取得的成绩建立于2005年《Nature Chemical Biology》所公布的研究结果的基础之上。2005年文章中,他们证明RNA能够在染色体水平关闭基因表达。新的研究中,研究人员跳出了基因表达方式的惯性思维。目前阻断基因表达的方法,如RNA干扰,原理是用RNA链阻止、绑定信使RNA。尽管RNA干扰研究基因表达效果显著,但Janowski认为,利用RNA在染色体水平控制活化和去活化过程会更有效。“它将目标转移到根源,到基因开启和关闭的源头。”
Corey说,许多研究人员保守地认为RNA只会以其它RNA为靶标,如信使RNA是RNA干扰的靶标。“这是大家熟知的,但是将RNA结合作为染色体的核酸调节器,在染色体水平,是一种新的主意,正在渐渐走入研究人员的视野。”(生物谷记者 子元)
部分英文原文:
Involvement of AGO1 and AGO2 in mammalian transcriptional silencing
Bethany A Janowski1, 2, Kenneth E Huffman1, 2, Jacob C Schwartz1, 2, Rosalyn Ram1, 2, Robert Nordsell1, 2, David S Shames1, 3, 4, John D Minna1, 3, 4 & David R Corey1, 2
1 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
2 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
3 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
4 Department of the Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
Duplex RNAs complementary to messenger RNA inhibit translation in mammalian cells by RNA interference (RNAi). Studies have reported that RNAs complementary to promoter DNA also inhibit gene expression. Here we show that the human homologs of Argonaute-1 (AGO1) and Argonaute-2 (AGO2) link the silencing pathways that target mRNA with pathways mediating recognition of DNA. We find that synthetic antigene RNAs (agRNAs) complementary to transcription start sites or more upstream regions of gene promoters inhibit gene transcription. This silencing occurs in the nucleus, requires high promoter activity and does not necessarily require histone modification. AGO1 and AGO2 associate with promoter DNA in cells treated with agRNAs, and inhibiting expression of AGO1 or AGO2 reverses transcriptional and post-transcriptional silencing. Our data indicate key linkages and important mechanistic distinctions between transcriptional and post-transcriptional silencing pathways in mammalian cells.
Inhibiting gene expression at transcription start sites in chromosomal DNA with antigene RNAs
Bethany A Janowski1,2, Kenneth E Huffman1,2, Jacob C Schwartz1,2, Rosalyn Ram