高级病生第7次课NoncodingRNAanddisease.ppt
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1、Noncoding RNA and Disease,Zhu-Zhong Mei, PhD Department of Pathophysiology,Central dogma of biology,protein,DNA,RNA,RNA and the genome - the end of the central dogma,25,000 protein coding genes in humans Protein-coding DNA = 12% of genome,The number of protein coding genes cannot justify the evoluti
2、onary gap between eukaryotes,Gene number,Transcript number,25k,15k,20k,6.5k,31k,30k,30k,Increase the complexity by increasing the combinatorial use of exons by alternative splicing,primary transcript,Alternative splicing,Function A,Isoform B,Isoform A,Function B,49k ?,20k,23k,6.5k,30k,Gene number,Tr
3、anscript number,Still the number of different transcripts cannot justify the evolutionary gap between eukaryotes,49k,The Old Guard,Holds steadfast to the idea that most of the transcription (like most of the DNA) is “Junk” Key reasoning: Little sequence conservation of non-coding RNA from species to
4、 species Explanation: Transcription of leftover retroviruses and RNA Polymerase infidelity,The Old Guard(holding onto a lack of science),Microarray data of mouse embryonic stem cells identified at least 945 long non-coding RNAs that are distinctly regulated with development and differentiation. (Din
5、ger, M. E. et al Genome Res. 2008, 18:14331445 ) Further analysis finds ncRNA to be tissue specific. (Furuno et al. 2006; Kapranov et al. 2002; Nakaya et al. 2007; Ravasi et al. 2006) And, its transcription responds to environmental stimuli. (Cawley et al. 2004; Louro et al. 2007; Ravasi et al. 2006
6、).,Continuing,Many have upstream transcriptional binding sites for proteins such as Sp1, c-Myc, p53, and Creb. (Cawley et al. 2004; Euskirchen et al. 2004) Long ncRNA with a known function, such as Xist, have very little sequence similarity. The same miRNA regulates different genes in different spec
7、ies (share little sequence homology/ rapid evolution theory). .these go on and on.,Eukaryotic RNA transcripts,tRNA rRNA snRNA tmRNA Rnase P RNA vRNAs gRNAs MRP RNA SRP RNAs Telomerase RNA,Transcription/chromatin structure regulators Post-transcriptional regulators Protein function modulators RNA/pro
8、tein localization regulators,RNA Transcripts,miRNA siRNA piRNA lncRNA,Protein-coding mRNA,Non-coding RNA Transcripts,snoRNAs,Housekeeping RNAs,Regulatory RNAs,micro (mi) RNA,Small RNAs ( 22 nucleotides in mature form). Encoded within regions of non protein-coding DNA or introns of traditional genes.
9、 Seed sequence: nucleotide positions 28 from the 5 end of miRNAs, which generally perfectly basepair with target mRNA. Mediate Post-transcriptional regulation of messenger RNAs. Complex set of proteins required for formation and processing of miRNA.,General knowledge of miRNAs,Found in wide range of
10、 plants and animal species. 1-5% of predicted genes humans (1000 total). Individual miRNAs are present at a level of 1,000 molecules/cell with some reaching 50,000. Estimated that 1/3 of protein coding genes are regulated by miRNAs. Cells shorten 3 UTR to dampen miRNA regulation of important genes a
11、t certain times.,The discovery of miRNAs,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).,Victor Ambros,Gary Ruvkun,Most genes identified from
12、a mutagenesis screens are protein-coding, but lin-4 encodes a 22-nucleotide non-coding RNA that is partially complementary to 7 conserved sites located in the 3-untranslated region (UTR) of the lin-14 gene.,The first discoered miRNA: lin-4,He L et al., Nature Review in Genetics, 2004, 5:522-531,lin-
13、4 vs lin-14: the first miR-target couple,Thought to be an oddity not a general phenomenon.,He L et al., Nature Review in Genetics, 2004, 5:522-531,Processing and maturation of miRNA,Principles of miRNA-mRNA interaction,Why all the fun for down-regulation? miRNA mediated TNF-alpha upregulation!,Vasud
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