1、生物信息學進展MicroRNA Systems Biology Targeting MicroRNAs With Small Molecules: From Dream to Reality生物信息學進展MicroRNA Systems BiologyIntroductionCentral dogma of molecular biologyChallenged by tiny fragments of noncoding RNAmiRNA, 22 nucleotides, negatively regulate protein-coding genes, central posttransc

2、riptional regulators of gene expressionVia imperfect base pairing to the 3UTR of target mRNAs: repression of protein production or mRNA degradationIntroductionHave been found in diverse plants, animals, some viruses and even algae (藻類) speciesAll multicellular eukaryotes, and perhaps some unicellula

3、r eukaryotes, utilize these RNAs to regulate gene expressionIntroductionSome researchers claimed that more than 1,000 miRNAs in human genome (Bentwich et al. 2005)718 miRNAs in human (2009-03)940 miRNAs in human (2010-04)1048 miRNAs in human (2011-04)1921 miRNAs in human (2012-03)2042 miRNAs in huma

4、n (2013-03)IntroductionExperimental 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)Estimated: more than one third of human genes are potentially regulated by miRNAsIntroductionThe following discoveries offe

5、r new insight into another layer of gene regulation；Animals that fail to produce certain mature miRNAs are unable to survive or reproduce；A single miRNA can be sufficient to cause cancer in mice (Costinean et al. 2006).內容microRNA的生物合成microRNA的生物功能microRNA與人類疾病microRNA調控細胞網絡microRNA對信號網絡調控microRNA對基因

6、調控網絡調控microRNA對代謝網絡調控microRNA對蛋白質互作網絡調控microRNA調控網絡的motif分析First discovered in C. elegansby Victor AmbrosTermed miRNAs19932001200220032004Uniformannotation systemRegistry database (miRBase)Individual miRNAexpression in variousspecies and tissuesFirst reportmiRNA expressionin cancersFirst application

7、 of array technologymacro-arrayRT PCRmicrobeadmicroarray2005Global picturein human cancers2007474 humanmiRNAsFebruary 1Other types ofnoncoding RNAIntegrationmiRNA with TFAt least800 miRNAs225 humanmiRNAsIn cancerBiological functions of miRNAsmiRNA emerges as a central regulator for developmentmiRNA

8、are involved in cell proliferation and apoptosismiRNA act as regulators for noise filtering and bufferingmiRNA might contribute to maintaining tissue identitymiRNAs in human diseasemiRNAs and heart diseasesLoss- or gain-of-function of specific miRNAs appears to be a key event in the genesis of many

9、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 al. 2007; Care et al. 2007; van Rooij et al. 2007)miRNAs in human diseasemiRNAs an

10、d 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 has diagnostic and perhaps prognostic potential (Lu et al. 2005; Calin and Croce, 20

11、06)miRNAs in human diseasemiRNAs 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 network concepts and their biological meaningsTypes and categories of cellular networks4 t

12、ypes of cellularnetworks in cellsprotein interaction networksgene regulatory networksmetabolic networkssignaling networksgeneral networkscellular specificnetworksfor all biological processesfor specific cellular activitiesBasic network concepts and their biological meaningsThe structures of cellular

13、 networks are scale-freeOne common structural property of cellular networks and other real-world networks is their scale-free topologyIn a scale-free network, a small number of nodes act as hubs, whereas most nodes have only a few links.They are robust (random removal) but also very vulnerable (targ

14、eted removal) to failure and attack (Barabasi and Albert, 1999; Barabasi and Oltvai, 2004)Principles of miRNA regulation of cellular networksmiRNA regulation of cellular signaling networksSignaling networks and computational analysisA signaling network is the most important complex system in process

15、ing 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 network triggers the responses of gene regulatory networksPrinciples of miRNA regulation of cellular netwo

16、rksmiRNA regulation of cellular signaling networksSignaling networks and computational analysisSignaling networks are presented as graphs containing both directed and undirected links Nodes represent proteins, directed links represent activation or inactivation relationships between proteins, while

17、undirected links represent simply physical interactions between proteinsStrategies of miRNA regulation of cellular signaling networks (Cui et al. 2006) the fraction of miRNA targets increases with the signal information flow from the upstream to the downstreamStrategies of miRNA regulation of cellul

18、ar signaling networks (Cui et al. 2006)miRNAs more frequently target positively linked network motifs and less frequently target negatively linked network motifsStrategies of miRNA regulation of cellular signaling networks (Cui et al. 2006)highly linked scaffold proteins have higher probability to b

19、e 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 proteins but provide regional organization for activation or inhibition between other proteinsmiRNA regulation of

20、gene regulatory networksWe 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 miRNAsThe complexity of GR by miRNAs at the post-transcriptional level is positively related to the complexity of GR by TFs a

21、t the transcriptional level in human genomeReasons: turn on more frequently, turn off more frequentlymiRNA regulation of metabolic networksThe information for metabolic pathways is more enriched than before. it possible to build comprehensive metabolic maps at this time (Feist et al. 2007)For a long

22、 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 amino acid biosynthesis, certain sugar and lipid metabolismsmiRNA regulation of metabolic networksmiRNAs often regul

23、ate 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 of the networkThese results imply that miRNA is strongly involved in coordinated regulation of metabolic processes in

24、metabolic networksmiRNA regulation of protein interaction networksmiRNAs preferentially regulate the proteins which have more interacting partners in the network (Liang and Li, 2007)Therefore, it makes sense that when a protein has more interacting protein partners, it will be regulated by more tran

25、scription factors and more miRNAsmiRNA regulation of protein interaction networksBroadly expressed mRNAs in different tissues tend to be regulated by more miRNAs (Yu et al. 2007a)Hub: intra-modular hub high CC inter-modular hub low CCInter-modular hub proteins are more likely to be regulated by miRN

26、AsReferences:1. MicroRNA Systems Biology. Edwin Wang.2. NETWORK BIOLOGY: UNDERSTANDING THE CELLS FUNCTIONAL ORGANIZATION. Albert-Lszl Barabsi & Zoltn N. Oltvai.3. MicroRNA expression profiling in cancer from a bioinformatics prospective. Yuriy Gusev & Daniel J Brackett生物信息學進展Targeting MicroRNAs With

27、 Small Molecules: From Dream to RealityNew therapy for diseases, particularly cancer, in humansmiRNAs as targets for cancer therapyAbnormalities in miRNAs are linked to the initiation, progression, and metastases of human cancersmiRNAs as targets for cancer therapyAbnormalities in miRNAs are linked

28、to the initiation, progression, and metastases of human cancersmiRNAs as targets for cancer therapyTherapeutic strategies based on modulation of miRNA expression hold great promise.miRNAs as targets for cancer therapymiRNAs as targets for cancer therapyA new way to target miRNAs: the use of small mo

29、leculesAs compared with proteins, RNA molecules have long been neglected as drug targetsmiRNAs appear to be “druggable”Stem loops and bulges facilitate targeting by small moleculesTissue specific expressionIncomplete base-pairingA new way to target miRNAs: the use of small moleculesA new way to targ

30、et miRNAs: the use of small moleculesIn silico discovery of small-molecule inhibitors of RNAsDrug discovery and development is an expensive and time-consuming processComputer-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