生物谷報道：德克薩斯大學(xué)西南醫(yī)學(xué)中心（UT Southwestern Medical Center）的研究人員最近發(fā)現(xiàn)了一種利用RNA改變基因活性的新途徑，為治療疾病和研究基因作用提供了新工具,。具體內(nèi)容刊登于《Nature Chemical Biology》,。
圍繞染色體DNA的蛋白混合物存在精微平衡,，控制基因的表達,。Bethany Janowski教授利用RNA動搖這種平衡,，激活培養(yǎng)細胞內(nèi)特定基因,。文章高級作者,、藥理學(xué)教授David Corey博士認為，這項研究的重要意義在于能夠確定誘哄基因進行表達的時間,。
基因是定居于染色體上的DNA片段,，攜帶編碼蛋白的指令，基因突變導(dǎo)致蛋白缺失、錯誤表達或者表達過量,，這些都可能導(dǎo)致疾病,。圍繞染色體的一團蛋白，幫助細胞確定那些基因進入轉(zhuǎn)錄階段,。UT Southwestern小組使用的RNA,，與乳腺癌細胞特異基因的DNA片段互補。將此RNA注入這些蛋白混合物,，特定基因被激活,，導(dǎo)致癌細胞生長速率下降。Corey博士認為,，新途徑的激活效果發(fā)生在染色體水平,，而非信使RNA水平，盡管注入的RNA鏈是人造的,，但此RNA與染色體相互作用的過程與肌體內(nèi)的天然過程相似,。具體機制尚待進一步分析。
Corey和Janowski如今取得的成績建立于2005年《Nature Chemical Biology》所公布的研究結(jié)果的基礎(chǔ)之上,。2005年文章中,，他們證明RNA能夠在染色體水平關(guān)閉基因表達。新的研究中,，研究人員跳出了基因表達方式的慣性思維。目前阻斷基因表達的方法,，如RNA干擾,，原理是用RNA鏈阻止、綁定信使RNA,。盡管RNA干擾研究基因表達效果顯著,，但Janowski認為，利用RNA在染色體水平控制活化和去活化過程會更有效,。“它將目標轉(zhuǎn)移到根源,，到基因開啟和關(guān)閉的源頭。”
Corey說,，許多研究人員保守地認為RNA只會以其它RNA為靶標,，如信使RNA是RNA干擾的靶標。“這是大家熟知的,，但是將RNA結(jié)合作為染色體的核酸調(diào)節(jié)器,，在染色體水平，是一種新的主意,，正在漸漸走入研究人員的視野,。”（生物谷記者 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
