高级病生NoncodingRNAanddiseasePPT学习教案

1、会计学1高级病生高级病生NoncodingRNAanddiseaseCentral dogma of biologyproteinDNARNA第1页/共45页第2页/共45页The number of protein coding genes cannot justify the evolutionary gap between eukaryotesGene numberTranscript number25k15k20k6.5k31k30k30kGene numberTranscript numberStill the number of different transcripts cann

2、ot justify the evolutionary gap between eukaryotes49k第5页/共45页第6页/共45页第7页/共45页第8页/共45页tRNArRNAsnRNAtmRNARnase P RNAvRNAsgRNAsMRP RNASRP RNAsTelomerase RNATranscription/chromatin structure regulatorsPost-transcriptional regulatorsProtein function modulatorsRNA/protein localization regulatorsRNA Transc

3、ripts miRNAsiRNApiRNAlncRNAProtein-coding mRNA Non-coding RNA Transcripts snoRNAsHousekeeping RNAs Regulatory RNAs Transcription/chromatin structure regulatorsPost-transcriptional regulatorsProtein function modulatorsRNA/protein localization regulatorsmiRNAsiRNApiRNAlncRNARegulatory RNAs 第9页/共45页第10

4、页/共45页第11页/共45页miRNA was first discovered in 1993 by Victor Ambros and Gary Ruvkun (published at the same issue of Cell).The second miRNA Let-7 was discovered in 2000 by Frank Slack as a postdoc at Harvard (Ruvkun lab).Gary Ruvkun第12页/共45页The first discoered miRNA: lin-4He L et al., Nature Review in

5、 Genetics, 2004, 5:522-531第13页/共45页lin-4 vs lin-14: the first miR-target coupleThought to be an oddity not a general phenomenon.He L et al., Nature Review in Genetics, 2004, 5:522-531第14页/共45页Processing and maturation of miRNA第15页/共45页第16页/共45页Vasudevan S. et al. Science 2007, 318:1931-1934第17页/共45页

6、miRNA and disease第18页/共45页Garzon R et al., Nature Reviews in Drug Discovery, 2010, 9:775-789miRNAs as oncogenes and tumor suppressors第19页/共45页microRNAsTumorigenesisDiagnosisPrognosismiR-9NeuroblastomamiR-10bBreast cancermiR-15, miR-15aLeukemia, pituitary adenomamiR-16, miR-16-1Leukemia, pituitary ad

7、enomamiR-17-5p, miR-17-92Lung cancer, lymphomamiR-20aLymphoma, lung cancermiR-21Breast cancer, cholangiocarcinoma, head & neck cancer, leukemiaPancreatic cancermiR-29, miR-29bLeukemia, cholangiocarcinomamiR-31Colorectal cancermiR-34aPancreatic cancerNeuroblastomamiR-96Colorectal cancermiR-98Head

8、 & neck cancermiR-103Pancreatic cancermiR-107Leukemia, pancreatic cancermiR-125a, miR-125bNeuroblastoma, breast cancermiR-128GlioblastomamiR-133bColorectal cancermiR-135bColorectal cancerCho WC et al. Int J Biochem Cell Biol 2010; Cho WC et al. Mol Cancer. 2007;6:60.第20页/共45页microRNAsTumorigenes

9、isDiagnosisPrognosismiR-143Colon cancermiR-145Breast cancer, colorectal cancermiR-146Thyroid carcinomamiR-155, has-miR-155Breast cancer, leukemia, pancreatic cancerLung cancermiR-181, imR-181a, imR-181b, imR-181cLeukemia, glioblastoma, thyroid carcinomamiR-183Colorectal cancermiR-184NeuroblastomamiR

10、-193Gastric cancermiR-196a-2Pancreatic cancermiR-221Glioblastoma, thyroid carcinomaPancreatic cancermiR-222Thyroid carcinomamiR-223LeukemiamiR-301Pancreatic cancermiR-376Pancreatic cancerlet-7, let-7a, let-7a-1, has-let-7a-2, let-7a-3Lung cancer, colon cancerLung cancerCho WC et al. Int J Biochem Ce

11、ll Biol 2010; Cho WC et al. Mol Cancer. 2007;6:60.第21页/共45页miRNA expression pattern changes during oncogenesis, and is unique for each cancer第22页/共45页miR-34 family as mediator of tumor suppression by p53Hermeking H et al., Cancer Cell, 2007, 12:414-418第23页/共45页Ma L et al., Nature cell biology, 2010,

12、 247miR-9, a MYC/MYCN activated microRNA, regulates E-cadherin and cancer metastasis第24页/共45页Cullen BR, Nature, 2009, 457:421-425Some viruses encode miRNAs第25页/共45页Nobel Prize in Physiology or Medicine 2006Andrew Z. FireCraig C. MelloC. elegans第26页/共45页nResults in target degradationtranslation arres

13、tsiRNAA comparison between miRNA and siRNA第27页/共45页A comparison between miRNA and siRNAHe L, Nature Review in Genetics, 2004, 5:522-531第28页/共45页lncRNA: long non-coding RNATranscripts longer than 200 nucleotides that have little or no protein-coding capacity. Long ncRNAs can regulate gene expression

14、through a diversity of mechanisms.Genomic organiztion of coding and non-coding transcriptsMercer TR, Nature Reviews in Genetics, 2009, 10:155-159第29页/共45页Functions of lnRNAsMercer TR, Nature Reviews in Genetics, 2009, 10:155-159第30页/共45页ncRNAs mediated X chromosome inactivation第31页/共45页lnRNA HOTAIR

15、reprograms chromatin state to promote cancer metastasisGupta RA, Nature, 2010, 464:1071-1076第32页/共45页Rate limitingstepamyloid precursor proteinBACE1-AS antisense RNA and Alzheimers Disease第33页/共45页(104 nts complete match)BACE1-AS upregulates the expression of BACE1Faghihi MA, Nature Medicine, 2008:

16、14, 723-730第34页/共45页St George-Hyslop P, Nature Medicine, 2008: 14, 711 - 712第35页/共45页Posttranscriptional regulation of PTEN dosage by noncoding RNAHe L, Science Signaling, 2010, 3: pe39第36页/共45页Candeinas MM et al. Nature cell biology, 2008, 10:1098第37页/共45页第38页/共45页Garzon R, Nature Reviews in Drug Discovery, 2010, 9:775-789第39页/共45页Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary