计算系统生物学导论系统生物学导论课件

1、计算系统生物学导论系统生物学导论课件计算系统生物学导论系统生物学导论课件How many RNAs in cells ?mRNA rRNA tRNAProteinsnRNAsnoRNAgRNA Antisense RNASRP-RNAmicroRNApRNARibozymeTelomerase RNA? 牛牛文库文档分享How many RNAs in cells ?mRNA Pnon-coding RNA (20-20000nt)RNAmRNAsmall non-coding RNA (sncRNA) (20-200nt)long non-coding RNA (lncRNA) (200)

2、牛牛文库文档分享non-coding RNARNAmRNAsmall nonNon-coding RNA: Versatility in form and functionNoncoding RNA genes are surprisingly numerous.Noncoding RNA have a very different functions. 牛牛文库文档分享Non-coding RNA: Noncoding RNA Time for RNomics 牛牛文库文档分享Time for RN PNAS, 97(26): 14035-14037, Dec 19, 2000Underst

3、anding RNomics from an expending snoRNA world 牛牛文库文档分享PNAS, 97(26): 14035-14037, DecCouzin J. Breakthrough of the year. Small RNAs make big splash.Science. 2002 Dec 20;298(5602):2296-7. 牛牛文库文档分享Couzin J. Breakthrough of DNA RNA ProteinGenomics ProteomicsStudy non-coding RNAs on the genomic scale RNo

4、micsStudy the identification, expression, biogenesis, structure, regulation of expression, targets, and biological functions of noncoding RNAs on the genomic scale. 牛牛文库文档分享DNA RNA ProteinG a hidden “RNA world” within modern DNA world 牛牛文库文档分享 a hidden “RNA world” wwwNovel classes of non-coding RNAs

5、 and cancer 牛牛文库文档分享Novel classes of non-coding RNSummarize newly discovered classes of ncRNAs highlight their functioning in cancer biology and potential usage as biomarkers or therapeutic targets 牛牛文库文档分享Summarize newly discovered Group: based on transcript sizeSmall ncRNAs Long ncRNAs 牛牛文库文档分享Gro

6、up: based on transcript Small non-coding RNAs 牛牛文库文档分享Small non-coding RNAswww.niuwkSmall non-coding RNAs 牛牛文库文档分享Small non-coding RNAswww.niuwkmicroRNA 牛牛文库文档分享microRNA 牛牛文库文档分享MicroRNAs account for 12% of the human genome and control the activity of 50% of all protein-coding genes be transcribed f

7、rom their own promoters and that miRNAs are generated by RNA polymerase II (RNAPII) as primary transcripts (pri-miRNAs) In the cytoplasm, the pre-miRNAs are processed to mature miRNAcharacteristic 牛牛文库文档分享MicroRNAs account for 12% ofMicroRNAs miRNA targeting in mammalian cells occurs predominantly t

8、hrough binding to sequences within 3UTRs ,however inhibition of gene expression through targeting the 5UTR regulate crucial cell processes such as proliferation,differentiation, and apoptosis cancers where miRNAs have been found to be also significant prognostic and predictive markersfunction 牛牛文库文档

9、分享MicroRNAs miRNA targeting in Piwi proteins associated RNAs Bind PiWi proteins; Dicer-independent mechanism; derived from complex DNA sequence elements; germ cell development stem cell self-renewal retrotransposon silencing 牛牛文库文档分享Piwi proteins associated RNAsSmall nucleolar RNAs enriched in the n

10、ucleolus located within introns of protein-coding genes and aretranscribed by RNA polymerase IIsource 牛牛文库文档分享Small nucleolar RNAs enrichedSmall nucleolar RNAs have important functions in the maturation of other noncoding RNAs manage post-transcriptional modification of rRNA and snRNA cellular targe

11、t mRNA, whose activity is regulated by snoRNA snoRNAs are critically associated with the development and progression of cancer 牛牛文库文档分享Small nucleolar RNAs have impLong non-coding RNAs 牛牛文库文档分享Long non-coding RNAswww.niuwk.Long non-coding RNAs Many identified lncRNA are transcribed by RNA polymerase

12、 II likely to be transcribed by polymerase IIIsource 牛牛文库文档分享Long non-coding RNAs Many ideLong 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 prote

13、in-coding gene expressionprocesses 牛牛文库文档分享Long non-coding RNAs alternatLong non-coding RNAsfour different mechanisms of lncRNAs actionlncRNAs can function as signals and regulate gene expressionAs Signals, lncRNA expression can faithfully reflect the combinatorial actions of transcription factors (

14、colored ovals) or signaling pathways to indicate gene regulation in space and time. . 牛牛文库文档分享Long non-coding RNAsfour diffeLong non-coding RNAsAs Decoys, lncRNAs can titrate away transcription factors and other proteins away from chromatin, or titrate the protein factors into nuclear subdomains. A

15、further example of decoys is lncRNA decoy for miRNA target sites Specifically, the 3UTR ofPTENP1RNA was found to bind the same set of regulatory miRNA sequences that normally target the tumor-suppressor genePTEN, reducing the downregulation ofPTENmRNA and allowing its translation into the tumor-supp

16、ressor protein PTEN 牛牛文库文档分享Long non-coding RNAsAs DecoysLong non-coding RNAslncRNAs can recruit chromatin-modifying enzymes to target genes and therefore function as guides. lncRNAs can recruit chromatin modifying enzymes to target genes, either in cis (near the site of lncRNA production) or in tra

17、ns to distant target genes. 牛牛文库文档分享Long non-coding RNAslncRNAs ca lncRNAs can bring together multiple proteins to form ribonucleoprotein complexes lncRNAs can bring together multiple proteins to form ribonucleoprotein complexes. The lncRNA-RNP may act on chromatin as illustrated to affect histone m

18、odifications. In other instances, the lncRNA scaffold is structural and stabilizes nuclear structures or signaling complexes 牛牛文库文档分享 lncRNAs can bring togetheLong intergenic noncoding RNAs lie within the genomic intervals between two genes lncRNAs could be utilized for cancer diagnosis , prognosis,

19、 and serve as potential therapeutic targets involved in tumorigenesis and cancer metastasis and imprintingprocesses function 牛牛文库文档分享Long intergenic noncoding RNAsLong intronic noncoding RNAscharacteristic Lie within the introns evolutionary conserved tissue and subcellular expression specificity 牛牛

20、文库文档分享Long intronic noncoding RNAsch functionLong intronic noncoding RNAs aberrantly expressed in human cancers possible link with posttranscriptional gene silencing 牛牛文库文档分享 functionLong intronic noncodLong ncRNAs with dual functionscharacteristic protein-coding Functionally regulatory RNA capacity

21、 deregulation in breast and ovarian tumors modulate gene expression through diverse mechanisms 牛牛文库文档分享Long ncRNAs with dual functionConclusions and future perspectives Small ncRNAs are involved mainly in the post-transcriptional gene regulation using translational repression or RNAi pathway Long nc

22、RNAs are much more involved in epigenetic regulation differential expression of ncRNAs is becoming recognized as 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 牛牛文库文档分享Conclusions and futu

23、re perspec The GENCODE v7 catalog of human long noncoding RNAs : Analysis of their gene structure, evolution, and expression 牛牛文库文档分享 The GENCODE v7 catalog of huThese lncRNAs can been further reclassified into the following locus biotypes based on their location with respect to protein-coding genes

24、1. 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） 牛牛文库文档分享These lncRNAs can been further2. LincRNA ： transcripts that are intergenic noncoding RNA loci with a length20

25、0 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) 牛牛文库文档分享2. LincRNA ： transcripts that 牛牛文库文档分享 牛牛文库文档分享Intergenic ,then subclassified accor

26、ding to its transcription orientation with the closest protein-coding gene (same sense, convergent, or divergent). 牛牛文库文档分享Intergenic ,then subclassifiedLncRNAs do not show evidence of protein-coding potential 牛牛文库文档分享LncRNAs do not show evidence oLncRNAs show lower and more tissue-specific expressi

27、on than protein-coding geneslncRNAs show lower expression in all tissues compared with mRNAs although lncRNAs show relatively high expression in testis 牛牛文库文档分享LncRNAs show lower and more ti 牛牛文库文档分享 牛牛文库文档分享LncRNAs also show more tissue-specific patterns compared with protein-coding genesThe majori

28、ty (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 tissue, and 11% are only detected in a single tissue) 牛牛文库文档分享LncRNAs also show more tissue-Almost 40% (3934 lncRNA genes, 5361 transcripts) of GENCODE lncRNAs i

29、ntersect 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 correlations of expression between these lncRNA genes and their host mRNAsCorrelation of expression between

30、overlapping lncRNAs and mRNAs 牛牛文库文档分享Correlation of expression betw We found that lncRNAs have more positive correlations with intersecting mRNAs elements than expected by chance 牛牛文库文档分享 We found that lncRNAs have mThere is mounting evidence that many lncRNAs are recruited to chromatin and epigene

31、tically 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 translationLncRNAs are enriched in the nucleus 牛牛文库文档分享There is mounting evid

32、ence thaIn 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 牛牛文库文档分享 牛牛文库文档分享We also tested whet

33、her particular classes of lncRNAintergenic, 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 lncR

34、NAintergenic, 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 transcripts 牛牛文库文档分享We also tested whether particuWe further investigated whether lncRNAs

35、are enriched in particular compartments within the nucleus（ chromatin ）. LncRNAs 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 t

36、hat lncRNAs are specifically recruited to chromatin, where they play a regulatory 牛牛文库文档分享We further investigated whetheLong noncoding RNAs are rarely translated in two human cell lines 牛牛文库文档分享Long noncoding RNAs are rarelyIntroductionsA 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 non-protein-coding. 牛牛文库文档分享IntroductionsA particular