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1、生物信息學(xué)進(jìn)展姜 偉外 語 學(xué) 館 411室MicroRNA Systems Biology Targeting MicroRNAs With Small Molecules: From Dream to Reality 生物信息學(xué)進(jìn)展姜偉MicroRNA Systems Biology Introductionv Central dogma of molecular biologyv Challenged by tiny fragments of noncoding RNAv miRNA, 22 nucleotides, negatively regulate protein-coding
2、genes, central posttranscriptional regulators of gene expressionv Via imperfect base pairing to the 3UTR of target mRNAs: repression of protein production or mRNA degradation IntroductionvHave been found in diverse plants, animals, some viruses and even algae (藻類) speciesvAll multicellular eukaryote
3、s, and perhaps some unicellular eukaryotes, utilize these RNAs to regulate gene expression IntroductionvSome researchers claimed that more than 1,000 miRNAs in human genome (Bentwich et al. 2005)v718 miRNAs in human (2009-03)v940 miRNAs in human (2010-04)v1048 miRNAs in human (2011-04)v1921 miRNAs i
4、n human (2012-03)v2042 miRNAs in human (2013-03) IntroductionvExperimental analysis: 100 to 200 target mRNAs are repressed and destabilized by a single miRNA (Krutzfeldt et al. 2005; Lim et al. 2005; Yu et al. 2007a)vEstimated: more than one third of human genes are potentially regulated by miRNAs I
5、ntroductionvThe following discoveries offer new insight into another layer of gene regulation；vAnimals that fail to produce certain mature miRNAs are unable to survive or reproduce；vA single miRNA can be sufficient to cause cancer in mice (Costinean et al. 2006). 內(nèi)容v microRNA的生物合成v microRNA的生物功能v mi
6、croRNA與人類疾病v microRNA調(diào)控細(xì)胞網(wǎng)絡(luò) microRNA對(duì)信號(hào)網(wǎng)絡(luò)調(diào)控 microRNA對(duì)基因調(diào)控網(wǎng)絡(luò)調(diào)控 microRNA對(duì)代謝網(wǎng)絡(luò)調(diào)控 microRNA對(duì)蛋白質(zhì)互作網(wǎng)絡(luò)調(diào)控 microRNA調(diào)控網(wǎng)絡(luò)的motif分析 First discovered in C. elegansby Victor Ambros Termed miRNAs1993 2001 2002 2003 2004Uniformannotation system Registry database (miRBase)Individual miRNAexpression in variousspecies a
7、nd tissues First reportmiRNA expressionin cancers First application of array technologymacro-arrayRT PCRmicrobeadmicroarray 2005 Global picturein human cancers 2007474 humanmiRNAsFebruary 1 Other types ofnoncoding RNAIntegrationmiRNA with TFAt least800 miRNAs 225 humanmiRNAsIn cancer Biological func
8、tions of miRNAsv miRNA emerges as a central regulator for developmentv miRNA are involved in cell proliferation and apoptosisv miRNA act as regulators for noise filtering and bufferingv miRNA might contribute to maintaining tissue identity miRNAs in human diseasevmiRNAs and heart diseasesLoss- or ga
9、in-of-function of specific miRNAs appears to be a key event in the genesis of many diverse diseasesFour recent papers showed that miRNAs (miR-1, miR-133, miR-208) are essential for heart development and regulating the expression of genes which take part in cardiac function (Yang et al. 2007; Zhao et
10、 al. 2007; Care et al. 2007; van Rooij et al. 2007) miRNAs in human diseasevmiRNAs and cancerHuman cancer studies are always the hotspots in life science research.Genome-wide studies of miRNA expression profiling showed that miRNA expression levels are altered in primary human tumors.miRNA profiling
11、 has diagnostic and perhaps prognostic potential (Lu et al. 2005; Calin and Croce, 2006) miRNAs in human diseasevmiRNAs and cancerCertain miRNAs could be tumor suppressorsLoss of miRNA let-7 in lung tumors correlates with high RAS (popular oncogenes) protein expression (Johnson et al. 2005) Basic ne
12、twork concepts and their biological meaningsv Types and categories of cellular networks4 types of cellularnetworks in cells protein interaction networksgene regulatory networksmetabolic networkssignaling networks general networkscellular specificnetworksfor all biological processesfor specific cellu
13、lar activities Basic network concepts and their biological meaningsv The structures of cellular networks are scale-free One common structural property of cellular networks and other real-world networks is their scale-free topology In a scale-free network, a small number of nodes act as hubs, whereas
14、 most nodes have only a few links. They are robust (random removal) but also very vulnerable (targeted removal) to failure and attack (Barabasi and Albert, 1999; Barabasi and Oltvai, 2004) Principles of miRNA regulation of cellular networksv miRNA regulation of cellular signaling networksSignaling n
15、etworks and computational analysisA signaling network is the most important complex system in processing the early extra- and intra-cellular signals in a cellOnce a cell receives signals, it processes the information, and finally the signals reach to transcription factors so that the signaling netwo
16、rk triggers the responses of gene regulatory networks Principles of miRNA regulation of cellular networksv miRNA regulation of cellular signaling networksSignaling networks and computational analysisSignaling networks are presented as graphs containing both directed and undirected links Nodes repres
17、ent proteins, directed links represent activation or inactivation relationships between proteins, while undirected links represent simply physical interactions between proteins Strategies of miRNA regulation of cellular signaling networks (Cui et al. 2006) the fraction of miRNA targets increases wit
18、h the signal information flow from the upstream to the downstream Strategies of miRNA regulation of cellular signaling networks (Cui et al. 2006)miRNAs more frequently target positively linked network motifs and less frequently target negatively linked network motifs Strategies of miRNA regulation o
19、f cellular signaling networks (Cui et al. 2006)highly linked scaffold proteins have higher probability to be targeted by miRNAsScaffold protein neutrally linked to other two proteins that are either positively or negatively connectedScaffold proteins do not directly activate or inhibit other protein
20、s but provide regional organization for activation or inhibition between other proteins v miRNA regulation of gene regulatory networks We uncovered a basic rule of miRNA regulation of gene regulatory networks: a gene that is regulated by more TFs is also more likely to be regulated by miRNAs The com
21、plexity of GR by miRNAs at the post-transcriptional level is positively related to the complexity of GR by TFs at the transcriptional level in human genome Reasons: turn on more frequently, turn off more frequently vmiRNA regulation of metabolic networksThe information for metabolic pathways is more
22、 enriched than before. it possible to build comprehensive metabolic maps at this time (Feist et al. 2007)For a long time, we have reasons to believe that the enzymes of metabolic networks are tightly controlled by transcription factorsmiRNAs selectively regulate certain metabolic processes such as a
23、mino acid biosynthesis, certain sugar and lipid metabolisms vmiRNA regulation of metabolic networksmiRNAs often regulate the last reaction step (LRS)once miRNAs regulate the LRS, the cut vertex are also enriched with miRNA targetsCut vertexes are in crucial network positions and become bottlenecks o
24、f the networkThese results imply that miRNA is strongly involved in coordinated regulation of metabolic processes in metabolic networks vmiRNA regulation of protein interaction networksmiRNAs preferentially regulate the proteins which have more interacting partners in the network (Liang and Li, 2007
25、)Therefore, it makes sense that when a protein has more interacting protein partners, it will be regulated by more transcription factors and more miRNAs vmiRNA regulation of protein interaction networksBroadly expressed mRNAs in different tissues tend to be regulated by more miRNAs (Yu et al. 2007a)
26、Hub: intra-modular hub high CC inter-modular hub low CCInter-modular hub proteins are more likely to be regulated by miRNAs References:1. MicroRNA Systems Biology. Edwin Wang.2. NETWORK BIOLOGY: UNDERSTANDING THE CELLS FUNCTIONAL ORGANIZATION. Albert-Lszl Barabsi & Zoltn N. Oltvai.3. MicroRNA expres
27、sion profiling in cancer from a bioinformatics prospective. Yuriy Gusev & Daniel J Brackett 生物信息學(xué)進(jìn)展Targeting MicroRNAs With Small Molecules: From Dream to RealityNew therapy for diseases, particularly cancer, in humans miRNAs as targets for cancer therapyvAbnormalities in miRNAs are linked to the in
28、itiation, progression, and metastases of human cancers miRNAs as targets for cancer therapyvAbnormalities in miRNAs are linked to the initiation, progression, and metastases of human cancers miRNAs as targets for cancer therapyvTherapeutic strategies based on modulation of miRNA expression hold grea
29、t promise. miRNAs as targets for cancer therapy miRNAs as targets for cancer therapy A new way to target miRNAs: the use of small moleculesvAs compared with proteins, RNA molecules have long been neglected as drug targetsvmiRNAs appear to be “druggable”Stem loops and bulges facilitate targeting by s
30、mall moleculesTissue specific expressionIncomplete base-pairing A new way to target miRNAs: the use of small molecules A new way to target miRNAs: the use of small moleculesvIn silico discovery of small-molecule inhibitors of RNAsDrug discovery and development is an expensive and time-consuming proc
31、essComputer-aided approaches can improve the efficiency of the drug pipeline dramatically in a cost-effective way (Docking programs: AutoDock and Dock) A new way to target miRNAs: the use of small moleculesvDiscovery of small-molecule inhibitors targeting miRNAsThe accurate determination or predicti
32、on of the 3D structures of miRNAs is the top priorityMC-fold/MC-Sym has been used successfully to accurately predict the double-helix region of several pre-miRNAs The potential impact of using small-molecule therapyv The identification of potent small-molecule inhibitors targeting miRNAs can lead to
33、 drug development for targeted cancer therapyv The computational effort will help to develop an integrated drug discovery platform, which will be made publicly available (database, methodology, and predictors) for knowledge disseminationv The accumulated knowledge and the drug discovery platform can
34、 be readily applied to the discovery of other miRNA-targeted small molecules The potential impact of using small-molecule therapyvThis development will be of immense helpDrug discoverymiRNA biologyComputational modelingBiological signaling pathway studiesMany other related areas Thank you!外 語 學(xué) 館 411室
生物信息學(xué)進(jìn)展教學(xué)：jw-生物信息學(xué)進(jìn)展
