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What are microRNAs? Morten Lindow
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Fire et al, Nature 1998 Worm embryo under phase contrast In situ staining for mex3 mRNA Mex3 inhibited with anti-sense RNA Mex3 inhibited with double stranded RNA
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Without small RNAs Transposons jump Stem cells are lost Brain and muscle fails to develop Plants succumb to viral infection Flowers take shapes unlikely to please a bee Cells fail to divide for lack of centromeres Insulin secretion is dysregulated
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miRNA logic ATCTGCCACCCTACAGAGTTTGACTTTTACCTCTGTAGTCATGCTGGTATTCAGGGCACTTCTCGACCTGCTCATTACCACGTTCTTTGGGATGAGAACAACTTTACTGCAGATGGACTTCAATCTCTGACCAATAACTTATGTTACACGTATGCAAGAT miRNA gene Pri-miRNA A microRNA Inhibit mRNA translation Drosha Dicer Export Pre-miRNA
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Additions to the Central Dogma Genome Transcriptome Proteome Regulation by proteins siRNA/miRNA Regulation by RNA Imprinting – methylation Splicing Ribozymes
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microRNAs quantified
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miRNA genes: genomic context +------------+----------+ | pos_type | count(*) | +------------+----------+ | antisense | 13 | | exonic | 5 | | intergenic | 109 | | intronic | 64 | +------------+----------+
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Some miRNAs occur in clusters
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miRNA targets Very few experimentally validated targets < 50 and mostly in fly and worm < 50 and mostly in fly and worm We have to rely on bioinformatic target predictions. Probably very noisy. 10% of all genes regulated by miRNAs ( Enright et al, 2003) 10% of all genes regulated by miRNAs ( Enright et al, 2003) 30% of all genes regulated by miRNAs (Lewis et al. 2004) 30% of all genes regulated by miRNAs (Lewis et al. 2004) ~all genes regulated to some degree (others) ~all genes regulated to some degree (others)
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Screen a lot of different cells/tissues Cancer vs. Normal. Differentiated vs non-differentiated Cancer vs. Normal. Differentiated vs non-differentiated Draw conclusions Cells of similar lineage have similar profiles Cells of similar lineage have similar profiles miRNAs are generally lower expressed in malignant (~undiffentiated) cells miRNAs are generally lower expressed in malignant (~undiffentiated) cells miRNA profiles can classify tumors (supposedly better than mRNAs) miRNA profiles can classify tumors (supposedly better than mRNAs) Interesting dataset!! Parallel expression information of both mRNA and miRNA in 90 samples
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Herpes virus microRNAs Kaposi Sarcoma Virus (10) Cytomegalo Virus (9) Epstein-Barr Virus (5) Mononucleosis Mononucleosis UUAAUGCUUAGCCUGUGUCCGA- (Ks.K9) UUAAUGCUAAUCGUG-AUAGGGG (Hs.155) CCAGCAGCACCUAAUCCAUCGG-- (Ks. K3-5p) -UAGCAGCACGUAAAU-AUUGGCG (Hs. 16) 5’3’
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microRNAs and hematopoesis Genome Biol. 2005;6(8):R71. Epub 2005 Aug 1
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microRNAs and stem cells Drosophila germline stem cells dcr-1 mutant has fewer clonal cysts than wt. Effect via Dap. Hatfield et. al., Nature 2005
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microRNAs and cardiogenesis Excess miR-1-1 decreased cardiomyocytes Effect is via miR-1-1 targeting of Hand2 transcription factor Zhao et al. Nature 2005
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microRNAs and brain Dicer mutants – do not process miRNA Rescued by injected mature miRNAs Giraldez et al, Science 2005
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