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1、The Introduction of Computational Systems Biology 计算系统生物学导论 Wang Dong Associate Professor Email:,What is noncoding RNA?,Non-coding RNA(ncRNA)is a RNA molecule that functions without being translated into a protein,How many RNAs in cells?,non-coding RNA(20-20000nt),RNA,mRNA,small non-coding RNA(sncRN
2、A)(20-200nt),long non-coding RNA(lncRNA)(200),Non-coding RNA:Versatility in form and function,Noncoding RNA genes are surprisingly numerous.,Noncoding RNA have a very different functions.,Time for RNomics,PNAS,97(26):14035-14037,Dec 19,2000,Understanding RNomics from an expending snoRNA world,Couzin
3、 J.Breakthrough of the year.Small RNAs make big splash.Science.2002 Dec 20;298(5602):2296-7.,DNA RNA Protein,Genomics,Proteomics,Study non-coding RNAs on the genomic scale,RNomics,Study the identification,expression,biogenesis,structure,regulation of expression,targets,and biological functions of no
4、ncoding RNAs on the genomic scale.,a hidden“RNA world”within modern DNA world,Novel classes of non-coding RNAs and cancer,Summarize newly discovered classes of ncRNAs,highlight their functioning in cancer biology and potential usage as biomarkers or therapeutic targets,Group:based on transcript size
5、,Small ncRNAs,Long ncRNAs,Small non-coding RNAs,Small non-coding RNAs,microRNA,MicroRNAs,account for 12%of the human genome and control the activity of 50%of all protein-coding genes,be transcribed from their own promoters and that miRNAs are generated by RNA polymerase II(RNAPII)as primary transcri
6、pts(pri-miRNAs),In the cytoplasm,the pre-miRNAs are processed to mature miRNA,characteristic,MicroRNAs,miRNA targeting in mammalian cells occurs predominantly through binding to sequences within 3UTRs,however inhibition of gene expression through targeting the 5UTR,regulate crucial cell processes su
7、ch as proliferation,differentiation,and apoptosis,cancers where miRNAs have been found to be also significant prognostic and predictive markers,function,Piwi proteins associated RNAs,Bind PiWi proteins;Dicer-independent mechanism;derived from complex DNA sequence elements;,germ cell development stem
8、 cell self-renewal retrotransposon silencing,Small nucleolar RNAs,enriched in the nucleolus located within introns of protein-coding genes and aretranscribed by RNA polymerase II,source,Small nucleolar RNAs,have important functions in the maturation of other noncoding RNAs,manage post-transcriptiona
9、l modification of rRNA and snRNA cellular target mRNA,whose activity is regulated by snoRNA,snoRNAs are critically associated with the development and progression of cancer,Long non-coding RNAs,Long non-coding RNAs,Many identified lncRNA are transcribed by RNA polymerase II likely to be transcribed
10、by polymerase III,source,Long non-coding RNAs,alternative splicing modulation of protein activity alternation of protein localization epigenetic regulation precursors of small RNAs and even tools for miRNAs silencingregulators of protein-coding gene expression,processes,Long non-coding RNAs,four dif
11、ferent mechanisms of lncRNAs action,lncRNAs can function as signals and regulate gene expressionAs Signals,lncRNA expression can faithfully reflect the combinatorial actions of transcription factors(colored ovals)or signaling pathways to indicate gene regulation in space and time.,Long non-coding RN
12、As,As Decoys,lncRNAs can titrate away transcription factors and other proteins away from chromatin,or titrate the protein factors into nuclear subdomains.A further example of decoys is lncRNA decoy for miRNA target sites Specifically,the 3UTR ofPTENP1RNA was found to bind the same set of regulatory
13、miRNA sequences that normally target the tumor-suppressor genePTEN,reducing the downregulation ofPTENmRNA and allowing its translation into the tumor-suppressor protein PTEN,Long non-coding RNAs,lncRNAs can recruit chromatin-modifying enzymes to target genes and therefore function as guides.lncRNAs
14、can recruit chromatin modifying enzymes to target genes,either in cis(near the site of lncRNA production)or in trans to distant target genes.,lncRNAs can bring together multiple proteins to form ribonucleoprotein complexes lncRNAs can bring together multiple proteins to form ribonucleoprotein comple
15、xes.The lncRNA-RNP may act on chromatin as illustrated to affect histone modifications.In other instances,the lncRNA scaffold is structural and stabilizes nuclear structures or signaling complexes,Long intergenic noncoding RNAs,lie within the genomic intervals between two genes,lncRNAs could be util
16、ized for cancer diagnosis,prognosis,and serve as potential therapeutic targets,involved in tumorigenesis and cancer metastasis and imprinting,processes,function,Long intronic noncoding RNAs,characteristic,Lie within the introns evolutionary conserved tissue and subcellular expression specificity,fun
17、ction,Long intronic noncoding RNAs,aberrantly expressed in human cancers possible link with posttranscriptional gene silencing,Long ncRNAs with dual functions,characteristic,protein-coding Functionally regulatory RNA capacity,deregulation in breast and ovarian tumors modulate gene expression through
18、 diverse mechanisms,Conclusions and future perspectives,Small ncRNAs are involved mainly in the post-transcriptional gene regulation using translational repression or RNAi pathway Long ncRNAs are much more involved in epigenetic regulation differential expression of ncRNAs is becoming recognized as
19、a one of the hallmarks of cancer cell ncRNAs have the promising potential in targeted regulation of gene expression and,therefore,in cancer targeted therapy,The GENCODE v7 catalog of human long noncoding RNAs:Analysis of their gene structure,evolution,and expression,These lncRNAs can been further re
20、classified into the following locus biotypes based on their location with respect to protein-coding genes1.Antisense RNAs：which have transcripts that intersect any exon of a protein-coding locus on the opposite strand,or publishedevidence of antisense regulation of a coding gene（3233）,2.LincRNA：tran
21、scripts that are intergenic noncoding RNA loci with a length200 bp（5094）3.overlapping transcripts:contain a coding gene within an intron on the same strand(unknow)4.intronic transcripts:reside within introns of a coding gene,but do not intersect any exons(378),Intergenic,then subclassified according
22、 to its transcription orientation with the closest protein-coding gene(same sense,convergent,or divergent).,LncRNAs do not show evidence of protein-coding potential,LncRNAs show lower and more tissue-specific expression than protein-coding geneslncRNAs show lower expression in all tissues compared w
23、ith mRNAs although lncRNAs show relatively high expression in testis,LncRNAs also show more tissue-specific patterns compared with protein-coding genesThe majority(65%)of protein-coding genes were detected in all HBM tissues compared with 11%of lncRNAs(21%of lncRNAs were not be detected in any tissu
24、e,and 11%are only detected in a single tissue),Almost 40%(3934 lncRNA genes,5361 transcripts)of GENCODE lncRNAs intersect protein-coding gene loci,and it is possible that such lncRNAs somehow contribute to the regulation of the latter(Fig.1B;Gingeras 2007;Pasmant et al.2011).We therefore computed co
25、rrelations of expression between these lncRNA genes and their host mRNAs,Correlation of expression between overlapping lncRNAs and mRNAs,We found that lncRNAs have more positive correlations with intersecting mRNAs elements than expected by chance,There is mounting evidence that many lncRNAs are rec
26、ruited to chromatin and epigenetically regulate gene expressionThus,we would expect that lncRNAs should be preferentially localized in the chromatin and nuclear RNA fractions,in contrast to protein-coding mRNAs that are trafficked to the cytoplasm for translation,LncRNAs are enriched in the nucleus,
27、In all cell lines,except for NHEK,we observed a robust and highly statistically significant enrichment of lncRNAs in the nucleus,compared with protein-coding mRNAs.Furthermore,the lncRNAs nuclear/cytoplasmic enrichment is consistent between cell types,We also tested whether particular classes of lnc
28、RNAintergenic,intronic,antisensehad distinct nuclear localization propensities,but we could find no significant difference,suggesting that nuclear enrichment is a general property of long non-protein-coding transcriptsWe also tested whether particular classes of lncRNAintergenic,intronic,antisenseha
29、d distinct nuclear localization propensities,but we could find no significant difference,suggesting that nuclear enrichment is a general property of long non-protein-coding transcripts,We further investigated whether lncRNAs are enriched in particular compartments within the nucleus（chromatin）.LncRN
30、As are significantly more enriched in chromatin than mRNAs:The median chromatin/nucleus expression ratio for lncRNAs is more than twice that of mRNAs(0.55 vs.0.26,respectively).This lends further support to the idea that lncRNAs are specifically recruited to chromatin,where they play a regulatory,Lo
31、ng noncoding RNAs are rarely translated in two human cell lines,Introductions,A particularly intriguing property of mammalian lncRNAs is their lack of evolutionary conservation,relative to protein-coding genes.It is importance of using empirical methodologies to document whether lncRNAs are actually
32、 non-protein-coding.,Results,In whole-cell RNA-seq data,lncRNA expression levels are on average 24-fold lower than mRNAsAll potentially translatable lncRNA ORFs had only a single peptide match,indicating low protein abundance and/or false-positive peptide matches.,Results,it remains possible that ex
33、tremely short or rapidly degraded polypeptides exist that have gone undetected.LncRNAs are 13-fold less likely to produce detectable peptides than similar mRNAs,indicating that 92%of GENCODE v7 lncRNAs are not translated in these two ENCODE cell lines.,Our group has broad research interests about no
34、n-coding RNA,cell death,cancer biology and bioinformatics.Using data-mining,statistics approaches and systems biology theories,et al,we will try to generate biological hypotheses and models,and then use systems biology approaches to validate and refine models and hypotheses.,Happiness Enthusiasm Positive,All the blessings we enjoy are the fruits of labor,toil,and self-denial,and study 我们得到的一切幸福都是劳动、辛苦、自我克制和学习的成果,
