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MicroRNA in Health and Disease
- 1. MicroRNA in HEALTH and PSYCHIATRIC DISORDERS By Moitrayee Majumder M.Phil Neuroscience 1st year
- 3. Outline • Introduction • Biogenesis • Versatility of miRNA • Function in regulation of gene expression • miRNA in Psychiatric disorder
- 4. Introduction • miRNA was first discovered in C. elegans in 1993 by Victor Ambros and RC Lee for Lin-4 gene regulating lin-14. • Predicted that 1-5% of human genome are precursors and regulate 30% of Protein- coding-genes. • 940 distinct miRNA molecules have been identified. • Non protein coding, endogenous RNAs of 21-22nt length. • Evolutionarily conserved • Regulate gene expression by binding complementary regions at 3’ regions of target mRNAs • Act as negative regulators of gene expression • miRNA expression profile is tissue specific
- 5. Types of RNA • small transfer RNA (tRNA) • Ribosomal RNA (rRNA) • Small nucleolar RNA (snoRNA) • Small interfering RNA (siRNA) • micro RNA (miRNA)
- 6. SiRNA and miRNA miRNA and siRNA are biochemically and functionally indistinguishable. miRNA are derived from a double stranded region of a 60-70 nucleotide hairpin RNA precursor and recognize multiple targets siRNA are derived from long double stranded RNA and are target specific Bartel Dp et al, Ambros V et al, Kim VN et al
- 7. MicroRNA biogenesis MacFurlane and Murphy, Current genomics, 2010
- 8. Gan et al, 2008 : Molecular Microbiology Drosha protein complex
- 9. Biogenesis contd.. In cytoplasm MacFurlane and Murphy, Current genomics, 2010
- 10. RISC loading Pratt et al, 2003 JBC
- 11. Slicer dependent Gene Silencing MacFurlane and Murphy, Current genomics, 2010
- 12. miRNA-mediated translational repression • Imperfect match between miRNA in RISC and target mRNAs • RISC usually binds 3’ UTR • Mechanism of inhibition… ???
- 13. Figure 4. Fold change and expression of hnRNPR and hnRNPH1 following their knock-down or over expression. Volk N, Shomron N (2011) Versatility of MicroRNA Biogenesis. PLOS ONE 6(5): e19391. doi:10.1371/journal.pone.0019391 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0019391
- 14. Figure 2. Fold change levels of mature and pre-miRNAs in transfected HeLa cells. Volk N, Shomron N (2011) Versatility of MicroRNA Biogenesis. PLOS ONE 6(5): e19391. doi:10.1371/journal.pone.0019391 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0019391
- 15. Diversity of miRNA functions • Development - Timing - Cell proliferation - Stem cell • Cell death • DNA methylation and chromatin formation • Diseases - Cancer - Diabetes - Cholesterol biosynthesis - Nervous system disorders - Autoimmune diseases - Metabolic diseases
- 16. miRNAs in Different cancers Bio geneX
- 18. Working hypothesis in etiology of psychiatric disorders Nature Medicine
- 19. Putative mi137 in Schizophrenia • GWAS and SNP for rs1625579 in postmortem studies have linked miR-137 with increased risk of Schizophrenia and Bipolar disease. • Controls with homozygous risk allele T had lower level of mature miR-137 in PFC against other combination of genotype. • miR 137 is implicated to role in neurogenesis and neuronal maturation. • Target for miR-137 includes CACNA1C, TCF4, CSMD1 to name a few • The minor allele carriers suffers from more negative symptoms viz social disinterest, speech disturbance and apathy. Orna Issler et al, 2015: Nature Review, NS Vol 16 Guella et al, 2013: JPR Vol 47 snRNU6 miRNA
- 20. Orna Issler et al, 2015: Nature Review, NS Vol 16
- 21. miR-1202 in Investigative MDD • Increasing evidence of altered patterns of circulating miRNAs are being associated with Psychiatric disorders. • miR-1202 is a primate-specific and brain- enriched microRNA involved in major depression and antidepressant treatment. • It can be used as biomarkers in blood of treatment (SSRIs) responders to distinguish from non-responders. • Other miRNAs viz miR-135a, miR-16 also showed down regulation in blood of depressive patients and up-regulated differentially in different treatment cohorts. • This suggests that, mode of action of antidepressant is mediated partially by miRNAs. Lopez et al, 2014: Nature Med 20
- 22. Using miRNA biology in diagnostics and therapeutics Orna Issler et al, 2015: Nature Review, NS Vol 16
Editor's Notes
- MiRNA precursors are commonly found in clusters through many different regions of genome, most frequently in intergenic and less in introns of protein coding genes. Intragenic miRNA genes can have its own pol II or pol III whereas intronic miRNA genes are transcripted by RNA pol II with the protein coding gene
- Drosha is a class of Ribonuclease, it forms the core nuclease in the microprocessor complex
- Dcp are P body complexes where mRNA are sequestered and decapped by Dcp activity and cleaved by Xrn1p exoribonuclease activity
- hnRNP- heterogenous ribonucleoprotein particle; RNA binding protein in nucleus; after splicing is done hnRNP remains bound to introns for their degradation which hoists the miRNA sequence. hnRNPR- has inhibitory role for siRNA biogenesis while hnRNPh1 has facilitatory role in the biogenesis
- KSRP- K type splicing regulatory protein
- Experiment on mice suggests role of miRNA in pure epigenetically modified psychiatric behaviour. miRNA from sperms of stressed father exogenously transfected in oocytes of otherwise healthy parents showed stress induced phenotypes simillar to stressed father