《计算系统生物学导论》系统生物学导论ppt课件

1、The Introduction of Computational Systems Biology 计算系统生物学导论计算系统生物学导论 Wang Dong Associate Professor : What is noncoding RNA?Non-coding RNA (ncRNA) is a RNA molecule that functions without being translated into a proteinHow many RNAs in cells ?mRNA rRNA tRNAProteinsnRNAsnoRNAgRNA

2、Antisense RNASRP-RNAmicroRNApRNARibozymeTelomerase RNA?non-coding RNA (20-20000nt)RNAmRNAsmall non-coding RNA (sncRNA) (20-200nt)long non-coding RNA (lncRNA) (200)Non-coding RNA: Versatility in form and functionNoncoding RNA genes are surprisingly numerous.Noncoding RNA have a very different functio

3、ns. Time for RNomicsPNAS, 97(26): 14035-14037, Dec 19, 2000Understanding RNomics from an expending snoRNA worldCouzin J. Breakthrough of the year. Small RNAs make big splash.Science. 2002 Dec 20;298(5602):2296-7. DNA RNA ProteinStudy non-coding RNAs on the genomic scale Study the identification, exp

4、ression, biogenesis, structure, regulation of expression, targets, and biological functions of noncoding RNAs on the genomic scale. a hidden “RNA world within modern DNA worldNovel classes of non-coding RNAs and cancerSummarize newly discovered classes of ncRNAs highlight their functioning in cancer

5、 biology and potential usage as biomarkers or therapeutic targetsGroup: based on transcript sizeSmall ncRNAs Long ncRNAsSmall non-coding RNAsSmall non-coding RNAsmicroRNAMicroRNAs account for 12% of the human genome and control the activity of 50% of all protein-coding genes be transcribed from thei

6、r 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 miRNAcharacteristicMicroRNAs miRNA targeting in mammalian cells occurs predominantly through binding to sequences within 3UTRs ,how

7、ever 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 markersfunctionPiwi proteins associated RNAs Bind PiWi proteins; Di

8、cer-independent mechanism; derived from complex DNA sequence elements; germ cell development stem cell self-renewal retrotransposon silencingSmall nucleolar RNAs enriched in the nucleolus located within introns of protein-coding genes and aretranscribed by RNA polymerase IIsourceSmall nucleolar RNAs

9、 have important functions in the maturation of other noncoding RNAs manage post-transcriptional modification of rRNA and snRNA cellular target mRNA, whose activity is regulated by snoRNA snoRNAs are critically associated with the development and progression of cancerLong non-coding RNAsLong non-codi

10、ng RNAs Many identified lncRNA are transcribed by RNA polymerase II likely to be transcribed by polymerase IIIsourceLong non-coding RNAs alternative splicing modulation of protein activity alternation of protein localization epigenetic regulation precursors of small RNAs and even tools for miRNAs si

11、lencingregulators of protein-coding gene expressionprocessesLong non-coding RNAsfour different 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 ova

12、ls) or signaling pathways to indicate gene regulation in space and time. . Long non-coding RNAs 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 mi

13、RNA target sites Specifically, the 3UTR of PTENP1 RNA was found to bind the same set of regulatory miRNA sequences that normally target the tumor-suppressor genePTEN, reducing the downregulation of PTEN mRNA and allowing its translation into the tumor-suppressor protein PTEN Long non-coding RNAslncR

14、NAs 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 trans to distant target genes. lncRNAs can bring together multiple proteins to form

15、ribonucleoprotein complexes lncRNAs can bring together multiple proteins to form ribonucleoprotein complexes. 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 compl

16、exes Long intergenic noncoding RNAs lie within the genomic intervals between two genes lncRNAs could be utilized for cancer diagnosis , prognosis, and serve as potential therapeutic targets involved in tumorigenesis and cancer metastasis and imprintingprocesses functionLong intronic noncoding RNAsch

17、aracteristic Lie within the introns evolutionary conserved tissue and subcellular expression specificity functionLong intronic noncoding RNAs aberrantly expressed in human cancers possible link with posttranscriptional gene silencingLong ncRNAs with dual functionscharacteristic protein-coding Functi

18、onally regulatory RNA capacity deregulation in breast and ovarian tumors modulate gene expression through diverse mechanismsConclusions and future perspectives Small ncRNAs are involved mainly in the post-transcriptional gene regulation using translational repression or RNAi pathway Long ncRNAs are

19、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 The GENCODE v7 catalog of human long

20、noncoding RNAs : Analysis of their gene structure, evolution, and expressionl2. LincRNA ： transcripts that are intergenic noncoding RNA loci with a length200 bp 5094l 3. overlapping transcripts : contain a coding gene within an intron on the same strand(unknow) l 4. intronic transcripts :reside with

21、in introns of a coding gene, but do not intersect any exons (378) l Intergenic ,then subclassified according to its transcription orientation with the closest protein-coding gene (same sense, convergent, or divergent).LncRNAs do not show evidence of protein-coding potentialLncRNAs show lower and mor

22、e tissue-specific expression than protein-coding geneslncRNAs show lower expression in all tissues compared with mRNAs although lncRNAs show relatively high expression in testisLncRNAs also show more tissue-specific patterns compared with protein-coding genesThe majority (65%) of protein-coding gene

23、s 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) Almost 40% (3934 lncRNA genes, 5361 transcripts) of GENCODE lncRNAs intersect protein-coding gene loci, and it is possible that such lncRN

24、As somehow contribute to the regulation of the latter (Fig. 1B; Gingeras 2007; Pasmant et al. 2021). We therefore computed correlations of expression between these lncRNA genes and their host mRNAsCorrelation of expression between overlapping lncRNAs and mRNAs We found that lncRNAs have more positiv

25、e correlations with intersecting mRNAs elements than expected by chanceThere is mounting evidence that many lncRNAs are recruited to chromatin and epigenetically regulate gene expressionThus, we would expect that lncRNAs should be preferentially localized in the chromatin and nuclear RNA fractions,

26、in contrast to protein-coding mRNAs that are trafficked to the cytoplasm for translationLncRNAs are enriched in the nucleusIn 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.Furthermor

27、e, the lncRNAs nuclear/cytoplasmic enrichment is consistent between cell types We also tested whether particular classes of lncRNAintergenic, intronic, antisensehad distinct nuclear localization propensities, but we could find no significant difference, suggesting that nuclear enrichment is a genera

28、l property of long non-protein-coding transcriptsWe also tested whether 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

29、-coding transcriptsWe further investigated whether lncRNAs 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

30、, respectively). This lends further support to the idea that lncRNAs are specifically recruited to chromatin, where they play a regulatoryLong noncoding RNAs are rarely translated in two human cell lines IntroductionslA particularly intriguing property of mammalian lncRNAs is their lack of evolutionary conservation, relative to protein-coding genes .lIt is importance of using empirical methodologies to document whether lncRNAs are actually non-protein-codi