Non coding RNA & diseases
- 1. NON-CODING RNA & DISEASES 1 Presented by: Sepideh Saroughi
- 2. Non-coding RNA • Not translated into a protein • tRNAs, rRNAs, microRNAs, siRNAs, piRNAs, snoRNAs, snRNAs, exRNAs, scaRNAs and Xist and HOTAIR. • NGS : New information about genomic organization & gene expression regulation History and discovery • Friedrich Miescher • Francis Crick • Alanine tRNA 2
- 3. 3
- 4. 4
- 5. 5
- 6. Biological roles • ncRNAs 1. In translation: Ribonucleoprotein 2. In RNA splicing: splicing reaction, self-splicing, snoRNA HBII-52 3. In DNA replication: Y RNAs, lupus erythematosus 4. In gene regulation: expression of genes, This regulation can occur in trans or in cis 5. In genome defense: piRNAs 6. Chromosome structure: Telomerase 7. As a hormone: ecdysone hormone, development of several endocrine organs 6
- 7. Roles in disease As with proteins, mutations or imbalances in the ncRNA repertoire within the body can cause a variety of diseases. 1. Cancer 2. Prader–Willi syndrome 3. Autism 4. Cartilage–hair hypoplasia 5. Alzheimer's disease 6. Autoimmune Diseases 7. Osteoporosis 7
- 8. 1. Cancer • Abnormal expression patterns • Chronic lymphocytic leukemia miR-16-1 and miR-15 primary • Non-small cell lung carcinoma rare SNP : mir-196a2 • Breast cancer miR-17 and miR-30c • Most important agent in preventing tumor p53 8
- 9. • Multifunctional regulators in all biological processes • ENCODE & FANTOM • Bioinformatic predictions suggest that human miRNAs regulate over 60% of transcripts. • Long noncoding RNAs • Lack functional open reading frames • Heterogeneous mechanisms • NATs 9
- 10. • MiRNAs: proliferation, resistance to apoptosis, angiogenesis, invasion and metastasis • CLL : miR‐15 and miR‐16 13q13.4 • More than 50% of human tumours: LOF p53 • HCC: MiR‐26a • Colon cancer: LIN28B • Long noncoding RNAs: malignant • MALAT1 NSCLC • HOTAIR colorectal, liver, pancreatic, breast and gastric cancers 10
- 11. • Sage • Microarray • RNA-seq • Cage • RT-qPCR • ISH • FISH • Northern blot analysis 11
- 12. 2. Prader–Willi syndrome • Deletion of the 29 copies of the C/D box snoRNA • Developmental disorder: over-eating & learning difficulties • Weak muscles, poor feeding & slow development • PWS is not generally inherited • Prader–Willi syndrome has no cure 12
- 13. The PW genes are the SNRPN and NDN necdin genes, along with clusters of snoRNAs: 1. SNORD64, SNORD107, SNORD108 2. two copies of SNORD109 3. 29 copies of SNORD116 4. 48 copies of SNORD115 13
- 14. 14
- 15. 15
- 17. 3. Autism(ASD) • Developmental disorder • rubella, alcohol, cocaine, pesticides, and air pollution • No treatment has been proven to cure ASD • SNORD115 gene cluster duplicated 17
- 18. 18
- 19. 19
- 20. • Inheritability of 45–56% • WES CNVs • CNVs may also lead to the generation of chimeric genes • Chimeric genes • Microdeletion • Recent studies have shown that epigenetic factors, including DNA methylation, hystone modifications and microRNAs (miRNAs), could play an important role in predisposition to autism. • Down-regulation of miR-6126 • Circular RNAs (circRNAs) NLGN1, STAG1, HSD11B1, VIP, and UBA6 20
- 21. 4. Cartilage–hair hypoplasia(CHH) • Mutations within RNase MRP A-to-G transition at nucleotide 70 • short stature, sparse hair, skeletal abnormalities and a suppressed immune system, Lymphopenia • PI3K-Akt signaling • G2 phase to mitosis 21
- 22. 22
- 23. 23
- 24. 5. Alzheimer's disease • BACE1 • Beta amyloid • miR‐29a: synaptic loss • miRNAs involved in the regulation of secretases: Aβ peptide • Wang : miR-107 • Overexpression of miR-188: reduced neuroinflammation, and improved long-term synaptic plasticity, spatial learning, and memory in the transgenic animals • miR-188, miR-339, miR-195, miR-186 24
- 25. 25
- 26. 26
- 27. 27
- 28. 6. Autoimmune Diseases • Ads are a family of disorders characterized by the body’s immune response being directed against its own tissues, with consequent chronic inflammation and tissue damage • HOX transcript antisense RNA (HOTAIR) • Overexpression of lncRNAs in T cells and B cells • GAPLINC • The circRNAs can interfere with miRNA functions • circRNAs may be diagnostic RA markers or potential therapeutic targets 28
- 29. 29
- 30. 30
- 31. 31
- 32. 32
- 33. 7. Osteoporosis • Osteoporosis is a common metabolic bone disease, influenced by genetic and environmental factors • miR-33-5p: osteoblastogenesis • miRNA-194: osteoblast differentiation • miR-96 33
- 34. 1. Noncoding RNAs in disease PMCID: PMC6174949 2. Non-coding RNAs in cancer: platforms and strategies for investigating the genomic “dark matter” 3. Noncoding RNAs in Alzheimer's disease. 4. Alzheimer Disease Pathogenesis: Insights From Molecular and Cellular Biology Studies of Oligomeric Aβ and Tau Species 5. Are Circulating MicroRNAs Peripheral Biomarkers for Alzheimer’s Disease? 6. Prader-Willi syndrome: reflections on seminal studies and future therapies. 7. Epigenetic therapy of Prader-Willi syndrome. 8. Prader-Willi-Like Phenotype Caused by an Atypical 15q11.2 Microdeletion 9. Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome 10. Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome 11. Targeted CRISPR disruption reveals a role for RNase MRP RNA in human preribosomal RNA processing 12. The human long non-coding RNA gene RMRP has pleiotropic effects and regulates cell-cycle progression at G2 13. Prediction and prioritization of autism-associated long non-coding RNAs using gene expression and sequence features 14. A heritable profile of six miRNAs in autistic patients and mouse models 15. An Overview of the Main Genetic, Epigenetic and Environmental Factors Involved in Autism Spectrum Disorder Focusing on Synaptic Activity 16. Genome-wide, integrative analysis of circular RNA dysregulation and the corresponding circular RNA-microRNA-mRNA regulatory axes in autism 17. Long Noncoding RNAs and Circular RNAs in Autoimmune Diseases 18. A micropeptide encoded by lncRNA MIR155HG suppresses autoimmune inflammation via modulating antigen presentation 19. Circular RNAs in immune responses and immune diseases 20. The roles of miRNA, lncRNA and circRNA in the development of osteoporosis 34