Computational Molecular Biology Biochem 218 BioMedical Informatics 231 http biochem218 stanford edu miRNA Regulatory Networks Doug Brutlag Professor Emeritus Biochemistry Medicine by courtesy Gene Regulatory Mechanisms Transcriptional Mechanisms o o Type of promoters RNA polymerase Control of Transcription Constitutive Inducible Repressible o Transcription Factors and TFBS Translational Mechanisms o Micro RNAs miRNAs and RITS complexes o Translational control mRNA degradation Promoter activation Silencer RNAs siRNAs RISC complexes degrading mRNA Epigenetic Mechanisms o o o Chromatin remodeling Histone modifications acetylation phosphorylation methylation DNA methylation Gene Expression Regulatory Network Yeast Regulatory Motifs Lee et al Science 298 799 804 2002 Prokaryotic Regulatory Genes Grow as the Square of the Total Number of Genes Mattick 2004 Nature Reviews Genetics 5 316 323 A Simplified History of Life on Earth Mattick 2004 Nature Reviews Genetics 5 316 323 Ratio of Non Protein Coding DNA to Protein Coding DNA During Evolution Mattick 2004 Nature Reviews Genetics 5 316 323 Conserved Regions in CFTR Intron Pheasant Mattick Genome Res 17 1245 1253 2007 microRNA Biogenesis Annu Rev Cell Dev Biol 2007 23 175 205 Biogenesis of miRNA Biogenesis of miRNA Filipowicz 2008 Nature Review Genetics 9 102 112 siRNA mediated siRNA and miRNA degradation of mRNA versus miRNA mediated inhibition of mRNA translation Filipowicz Curr Op Structural Biology 15 331 341 2005 Initiation of Translation Filipowicz 2008 Nature Review Genetics 9 102 112 Mechanisms of Translational Regulation by miRNP Complexes Filipowicz 2008 Nature Review Genetics 9 102 112 miRNAs Inhibit Translation by Inducing Ribosome Drop Off Petersen et al 2006 Molecular Cell 21 533 542 miRNA Expression Results in Temporal and Spatial Reciprocity with Target Expression Annu Rev Cell Dev Biol 2007 23 175 205 Genomic Organization of miRNA Genes Intronic miRNAs often in antisense direction made from own promoter Exonic miRNAs non coding or in alternatively spliced exons Zhao Y Srivastava D TIBS 32 189 2007 Precursor miRNA Products Form Stem Loop Structures Dicer Structure Function Dicer Movie Filipowicz Curr Op Structural Biology 15 331 341 2005 Argonaute Structure and Function Martin Jinek Jennifer A Doudna Nature 457 405 412 22 January 2009 Recognition of RNA Termini by Argonaute Martin Jinek Jennifer A Doudna Nature 457 405 412 22 January 2009 Homology Between C elegans and Human miRNAs Homology Between C elegans and Homo sapiens miRNAs Lim 2003 Genes Dev 17 991 Predicted miRNA Precursors Lim 2003 Genes Dev 17 991 1008 miRBase http www mirbase org miRBase Genome Browser http www mirbase org cgi bin browse pl miRBase Human miRNAs http www mirbase org cgi bin mirna summary pl org hsa miRBase Human let 7a 1 http www mirbase org cgi bin mirna entry pl acc MI0000060 miRBase Human let 7a 1 Page 2 http www mirbase org cgi bin mirna entry pl acc MI0000060 miRBase MicroCosm miRNA Targets http www ebi ac uk enright srv microcosm htdocs targets v5 miRBase MicroCosm miRNA Targets http www ebi ac uk enright srv microcosm htdocs targets v5 MicroCosm miRNA Targets Prediction http www ebi ac uk enright srv microcosm htdocs targets v5 info htm miRViewer http people csail mit edu akiezun miRviewer miRViewer mir 10 family http people csail mit edu akiezun miRviewer mir 10 index html miRViewer mir 10 Alignment http people csail mit edu akiezun miRviewer mir 10a align html Human miRNAs February 22 2010 Total miRNA genes in 115 species Total number of miRNAs known Number human miRNAs identified Number of human mRNA targets 10 882 1 580 851 34 788 miRNAs can have multiple targets Target mRNAs can have multiple miRNA binding sites miRBase http www mirbase org MicroCosm http www ebi ac uk enright srv microcosm miRNAs Affect Everything Frank Slack frank slack yale edu Micro RNAs Regulate Cell Growth and Death Frank Slack frank slack yale edu miRNAs as Oncogenes and Tumor Supressors Zhang et al Dev Biol 2007 Feb 1 302 1 1 12 Zhang et al Dev Biol 2007 Feb 1 302 1 1 12 MicroRNAs and Human Cancer George Calin miRNAs Involved in Human Cancer Croce Nat Rev Genet 2009 Oct 10 10 704 14 Croce Nat Rev Genet 2009 Oct 10 10 704 14 miRNA Oncogenes or Tumor Suppressor Genes Croce Nat Rev Genet 2009 Oct 10 10 704 14 Croce Nat Rev Genet 2009 Oct 10 10 704 14 miRNA Dysregulation in Human Cancers Croce Nat Rev Genet 2009 Oct 10 10 704 14 Croce Nat Rev Genet 2009 Oct 10 10 704 14 cMyc miRNAs Regulate E2F1 Cell Cycle TF Zhang et al Dev Biol 2007 Feb 1 302 1 1 12 Zhang et al Dev Biol 2007 Feb 1 302 1 1 12 miRNA 17 92 Cluster Activated by Myc O Donnell et al Nature 2005 435 839 843 Myc Represses Most Other miRNAs George Calin miRNA 17 92 induces lymphomagenesis miRNAs as Cancer Diagnostics George Calin miRNA Profiling Using Custom Microarrays Frank Slack frank slack yale edu miRNAs and Cancer A Summary miRNAs control cell cycle cell differentiation and apoptosis by regulating oncogenes and tumor supressor genes miRNAs are misexpressed in cancer and are therefore excellent diagnostic prognostic markers in cancer Some miRNAs e g mir 155 can cause cancer and oncogenic miRNAs may be therapeutic targets in cancer Other miRNAs like let 7 may prevent cancer and may be therapeutic molecules themselves MicroRNAs could augment current cancer therapies Frank Slack frank slack yale edu miRNAs Involved in Many Diseases George Calin References Role of miRNAs in Cancer and Apoptosis Lynan Lennon Biol Rev Camb Philos Soc 2009 Feb 84 1 55 71 Causes and consequences of microRNA dysregulation in cancer Croce Nat Rev Genet 2009 Oct 10 10 704 14 miRNAs as oncogenes and tumor suppressors Zhang Dev Biol 2007 Feb 1 302 1 1 1 Transcriptional regulatory networks in Saccharomyces cerevisiae Lee Science 2002 Oct 25 298 5594 799 804 RNA regulation a new genetics Mattick Nat Rev Genet 2004 Apr 5 4 316 23 microRNA functions Bushati Annu Rev Cell Dev Biol 2007 23 175 205 Mechanisms of post transcriptional regulation by microRNAs are the answers in sight Filiowicz Nat Rev Genet 2008 Feb 9 2 102 14 Post transcriptional gene silencing by siRNAs and miRNAs Filipowicz Curr Opin Struct Biol 2005 Jun 15 3 331 41 The microRNAs of Caenorhabditis elegans Lim Genes Dev 2003 Apr 15 17 8 991 1008 A three dimensional view of the molecular machinery of RNA interference Jinek Nature 2009 Jan 22 457 7228 405 12 miRNAs and Cancer AAAI Science Webinars February 20 with George Calin Brank Slack and Scott Hammond Short RNAs
View Full Document
Unlocking...