生物谷報(bào)道：11月13日美國愛荷華州大學(xué)的科學(xué)家發(fā)現(xiàn)了微小RNA表達(dá)的新機(jī)制,。微小RNA是RNA的短片段,，不能翻譯成蛋白質(zhì),，但對蛋白質(zhì)的翻譯有調(diào)節(jié)作用,。Davidson及同事的研究不僅發(fā)現(xiàn)了微小RNA的不同于目前所了解的表達(dá)方式,，還發(fā)現(xiàn)某些垃圾基因根本不是垃圾，而是由能產(chǎn)生微小RNA的序列組成的,。
與原先估計(jì)的不同,，他們發(fā)現(xiàn)微小RNA表達(dá)的分子機(jī)制與翻譯為蛋白質(zhì)的RNA表達(dá)的分子機(jī)制不同。微小RNA的表達(dá)需要RNA多聚酶III,，而翻譯為蛋白質(zhì)的RNA的表達(dá)則需要RNA多聚酶II,。研究結(jié)果發(fā)表在11月12日的自然結(jié)構(gòu)及分子生物進(jìn)展網(wǎng)絡(luò)版。
許多RNA并不產(chǎn)生蛋白質(zhì),，卻調(diào)控蛋白質(zhì)的產(chǎn)生,，非編碼RNA、如微小RNA代表了一組精細(xì)的控制開關(guān),，人類基因中已確認(rèn)了450多鐘微小RNA,。了解微小RNA是如何工作的,，及對微小RNA自身的調(diào)控,，可能對生物學(xué)和醫(yī)學(xué)的許多領(lǐng)域有重要意義。”
來源：愛荷華大學(xué)
英文原文：
University of Iowa Scientists Explore Function of 'Junk DNA'
University of Iowa scientists have made a discovery that broadens understanding of a rapidly developing area of biology known as functional genomics and sheds more light on the mysterious, so-called "junk DNA" that makes up the majority of the human genome.
The team, led by Beverly Davidson, Ph.D., a Roy J. Carver Biomedical Research Chair in Internal Medicine and UI professor of internal medicine, physiology and biophysics, and neurology, have discovered a new mechanism for the expression of microRNAs -- short segments of RNA that do not give rise to a protein, but do play a role in regulating protein production. In their study, Davidson and colleagues not only discovered that microRNAs could be expressed in a different way than previously known, they also found that some of the junk DNA is not junk at all, but instead consists of sequences that can generate microRNAs.
Davidson and her colleagues, including Glen Borchert, a graduate student in her lab, investigated how a set of microRNAs in the human genome is turned on, or expressed. In contrast to original assertions, they discovered that the molecular machinery used to express these microRNAs is different than that used to express RNA that encodes proteins. Expression of the microRNAs required an enzyme called RNA Polymerase III (Pol III) rather than the RNA Polymerase II (Pol II), which mediates expression of RNA that encode proteins. The study is published in Nature Structural and Molecular Biology Advance Online Publication (AOP) on Nov. 12.
"MicroRNAs are being shown to play roles in cancer and in normal development, so learning how these microRNAs are expressed may give us insight into these critical biological processes," said Borchert, who is lead author of the study. "Up to now it's been understood that one enzyme controls their expression, and we now show that in some cases it's a completely different one."
Genes that code for proteins make up only a tiny fraction of the human genome. The function of the remaining non-coding sequence is just beginning to be unraveled. In fact, until very recently, much of the non-coding sequence was dismissed as junk DNA. In 1998, scientists discovered that some DNA produced small pieces of non-coding RNA that could turn off, or silence, genes. This discovery won Andrew Fire and Craig Mello the 2006 Nobel Prize for medicine or physiology. Since their discovery, the field has exploded and small, non-coding RNAs have been shown to play an important role in development and disease in ways that scientists are only just beginning to understand.
"Not so many years ago our understanding was that DNA was transcribed to RNA, which was then translated to protein. Now we know that the levels of control are much more varied and that many RNAs don't make protein, but instead regulate the expression of proteins," Davidson explained. "Non-coding RNA like microRNAs represent a set of refined control switches, and understanding how microRNAs work and how they are themselves controlled is likely to be very important in many areas of biology and medicine."
Over 450 microRNAs have been identified in the human genome. Learning how they are turned on and in what cells and what they do, may allow scientists to turn that knowledge to their advantage as a medical tool.
作者簡介：
Beverly Davidson博士是內(nèi)科Roy J. Carver生物醫(yī)學(xué)研究會(huì)主席、愛荷華大學(xué)內(nèi)科,、生理,、生物物理、神經(jīng)學(xué)教授,。
Beverly Davidson, Ph.D. (Full Member)
Roy J Carver Professor in Internal Medicine, University of Iowa, Iowa City, IA
Director, Gene Transfer Vector Core, University of Iowa, Iowa City, IA
Professor in Neurology, Physiology & Biophysics, University of Iowa, Iowa City, IA
Co-Director, Iowa Biosciences Advantage Program, University of Iowa, Iowa City, IA
http://www.medicine.uiowa.edu/Davidsonlab/index.html
Research Interest
Dr. Davidson's research in gene transfer includes vector development and performing experiments to better understand the current barriers to gene transfer to lung, liver, brain, and hematopoietic and neural stem cells. In her collaborations with Drs. Zabner and McCray, she has focused on improving gene transfer to the apical surface of human airway epithelia for treatment of CF. Studies with Dr. Zabner are focused on gene transfer using encapsidated viruses, such as adenovirus and AAV. Experiments with Dr. McCray are directed at lentivirus and MMLV-based retrovirus applications. In recent studies Dr. Davidson and colleagues have identified and characterized major barriers to application of AAV2, adenovirus type 5, and many envelopes available for pseudotyping retrovirus vectors. In subsequent studies novel envelopes, or novel encapsidated viruses, have been evaluated in their abilities to overcome these limitations.
Wang, G., Williams, G., Xia, H., Hickey, M., Shao, J., Davidson, B.L., and McCray, P.B. 2002. Apical barriers to airway epithelial cell gene transfer with amphotropic retroviral vectors. Gene Ther 9:922-931
Zabner, J., Seiler, M., Walters, R., Kotin, R.M., Fulgeras, W., Davidson, B.L., and Chiorini, J.A. 2000. Adeno-associated virus type 5 (AAV5) but not AAV2 binds to the apical surfaces of airway epithelia and facilitates gene transfer. J Virol 74:3852-3858
Zabner, J., Chillon, M., Grunst, T., Moninger, T.O., Davidson, B.L., Gregory, R., and Armentano, D. 1999. A chimeric type 2 adenovirus vector with a type 17 fiber enhances gene transfer to human airway epithelia. J Virol 73:8689-8695
Wang, G., Slepushkin, V., Zabner, J., Keshavjee, S., Johnston, J.C., Sauter, S.L., Jolly, D.J., Dubensky, T.W., Jr., Davidson, B.L., and McCray, P.B., Jr. 1999. Feline immunodeficiency virus vectors persistently transduce nondividing airway epithelia and correct the cystic fibrosis defect. J Clin Invest 104:55-62
Research in Dr. Davidson's laboratory is also focused on inherited genetic diseases that cause central nervous system dysfunction, with a focus on (1) recessive, childhood onset neurodegenerative disease, in particular the lysosomal storage diseases such as the mucopolysaccharidoses and Battens disease; and (2) dominant genetic diseases for example the CAG repeat disorders, Huntington?s disease and spinal cerebellar ataxia type I. Research on childhood onset neurodegenerative diseases is focused on experiments to better understand the biochemistry and cellular trafficking of proteins deficient in these disorders, and to develop gene and cell-based medicines for therapy. Gene therapy studies are focused on vector development, emphasizing the study of novel envelopes for cellular targeting of lentivirus vectors, or non-traditional capsid proteins for encapsidated vectors (AAV and adenovirus). Therapies for dominant disorders are an exciting challenge and require that the dominant disease allele be silenced. To approach this, we have developed vectors expressing small inhibitory RNA, or siRNA. These small RNAs lead to the degradation of the targeted sequence. We have shown that siRNA reduces expression of the target in cell culture models of CAG repeat diseases, leading to an improved phenotype. Current studies are determining the effectiveness of in vivo delivered siRNA to correct disease manifestations in relevant models.
Xia, H., Mao, Q., Paulson, H.L., and Davidson, B.L. 2002. siRNA-mediated gene silencing in vitro and in vivo. Nat Biotechnol 20:1006-1010.
Brooks, A.I., Stein, C.S., Hughes, S.M., Heth, J., McCray, P.M., Jr., Sauter, S.L., Johnston, J.C., Cory-Slechta, D.A., Federoff, H.J., and Davidson, B.L. 2002. Functional correction of established central nervous system deficits in an animal model of lysosomal storage disease with feline immunodeficiency virus-based vectors. Proc Natl Acad Sci U S A 99:6216-6221.
Hughes SM, Moussavi-Harami F, Sauter SL, Davidson BL. Viral mediated gene transfer to mouse primary neural progenitor cells. Mol Ther In Press 2002. Cover.
Yang, G.S., Schmidt, M., Yan, Z., Lindbloom, J.D., Harding, T.C., Donahue, B.A., Engelhardt, J.F., Kotin, R., and Davidson, B.L. 2002. Virus-mediated transduction of murine retina with adeno-associated virus: effects of viral capsid and genome size. J Virol 76:7651-7660.
Publications from Genetherapy Center
Publications from PubMed
