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RNA Interference: Unraveling Cellular Secrets

Explore the groundbreaking discovery of RNA interference by Fire and Mello in C. elegans, its mechanisms in gene silencing, biogenesis of small interfering RNAs (siRNAs) and microRNAs, and its potential therapeutic applications in various diseases. Discover how these small RNA molecules regulate gene expression and impact diverse cellular processes. Dive into the intricate world of miRNAs, their tissue-specific functions, and the emerging field of nanobiotechnology for siRNA delivery in targeted therapeutics. Delve into the complexities of miRNA profiles in diseases and the promising yet challenging prospects of harnessing RNA interference for personalized medicine.

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RNA Interference: Unraveling Cellular Secrets

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  1. Nobel price 2006 "for their discovery of RNA interference - gene silencing by double-stranded RNA" Andrew Z. Fire Craig C. Mello

  2. Serendipity? Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegansAndrew Fire, SiQun Xu, Mary K. Montgomery,Steven A. Kostas, Samuel E. Driver & Craig C. Mello NATURE | VOL 391 | 19 FEBRUARY 1998 They worked on something else in C. elegans Gene expression – sense RNA (control) Gene silencing – antisense RNA (weak effect) One more controla with double strand (s-as) RNA, SURPRISE – IT WORKED VERY WELL

  3. Nobelova price experiment dsRNA blocks target mRNA asRNS dsRNS

  4. Not absolute new Drosophila (Elbashir, EMBO J, 2001, Genes and Dev, 2001) dsRNA → 21-23 nt small dsRNA small interferring RNA – siRNA siRNS 21-25 nt dsRNA from a bigger dsRNA precursor molecule

  5. These are coded in genome – also in ours C. elegans (Lee, 1993, Cell) NON CODING SEQUENCES! SMALL (61 → 22nt) RNA lin-14 mRNS 3’ UTR komplementerita REGULATION OF GENE EXPRESSION microRNA (miRNA)

  6. miRNS biogenesis The code is transcribed by RNA polymerase II More possibilities – separated - 1 miRNA – clusters – in INTRONS! Mendell, 2008, Cell

  7. Biogenesis and effect of siRNA Dykxhoorn, 2003, Nat Rev Mol Cell Biol

  8. Finalisation of siRNA • With proteincomplexes (coded in genome) • Dicer makes siRNA (+ATP) • RISC – komplex with siRNA, cuts mRNA(+ATP) • Argonauta – blocks translation

  9. siRNA effect Eckstein, 2005, TIBS

  10. Another possibility Inhibícia translácie

  11. miRNA - functions In human genome at least 500 – 1000 miRNa genes 1-1,5 % of all structural genes A new (?) form of gene expression regulation – on the interface of transcription and translation THE LAST CHECKPOINT (SMALL NINJA POLICIMEN) miRNA expression regulation???? tissue specificity, dependent on ontogenesis Involved in Development, differentiation, apoptosis, cell cycle

  12. miRNA functions One miRNA can regulate more mRNA (Lim, 2005, Nature) In different conditions different picture of expression miR-1 – heart, miR-124 – brain In vitro experiments miR-1 96, miR124 downregulated 174 génov

  13. miRNA and disease miRNA profiles different in normal and malignant cells miRNA profiles in diabetes, cardiovascular and kidney diseases, degenerative disease of CNS – intensive research currently without aplication in practical medicine SNPs in miRNA genes and disease??? Therapeutical perspectives? Malignancies Farmakogenetics Design of artifical siRNA? Not a simple task Get them to the proper place – nanobiotechnology

  14. Fewell, 2006, Drug Discovery

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