Non-coding RNA in human health and disease

Question 1

non-coding RNA

Answer 1

a RNA molecule that does not encode a protein

Question 2

long-non-coding RNA

Answer 2

longer than 200 nt, poor sequence conservation (except for telomeric RNA), less complex species have fewer

• tissue/individual/developmental specifity
• functional, scaffold, guide
• X-chromosome inactivation in females
• embryonic stem cell/progenitor cell maintenance/differentiation

Question 3

intergenic lncRNA

Answer 3

antisense (intronic, exonic), sense (intronic)

Question 4

eRNAs

Answer 4

enhancer RNAs

Question 5

paRNA

Answer 5

promoter-associated RNA

Question 6

how do miRNAs regulate gene expression?

Answer 6

-guide RISC complex to mRNA through basepairing with 3’UTR. depending on degree of complimentarity, this will cause either:
-degradation of mRNA
-mRNA cleavage
-inhibition of protein synthesis from targeted mRNA
-> regulate gene expression post-transcriptionally
(one miRNA can target many mRNAs, one mRNA can be targeted by many miRNAs)

Question 7

role of ncRNAs in disease

Answer 7

abberant expression levels of ncRNAs can shift the chemical equilibrium in cells, causing disease (failure of binding to intended protein partner in ribonucleic complexes

Question 8

how are downregulated miRNA levels in disease treated?

Answer 8

• DNA demethylating agent/HDAC inhibitors (for miRNA re-expression
• miRNA virus delivery systems
• drugs that enhance miRNA expression

Question 9

how are upregulated miRNA levels in disease treated?

Answer 9

• complementarity-based miRNA inhibition
• synthetic anti-miRNAs
• miRNA-sponges

Question 10

examples of non-coding RNA contributing to disease

Answer 10

• cancer and Alzheimer’s disease (lncRNA)
• oncogenes (miRNA)
• infertility (piRNAs) - PIWI mutation

Question 11

benefits of using RNA molecules as medicine

Answer 11

• affect protein expression, fix errors in protein production
• potential targets: pain receptors, inhibition of harmful genes, viruses
• easy and cheap to synthesize
• usable against undruggable targets
• so far no evidence of adaptive immune response
• easy to combine
• suitable for personalized medicine

Question 12

challenges of using RNA molecules as medicine

Answer 12

• intracellular delivery across cell and endosomal membranes
• poor pharmacokinetic properties, partly due to urinary excretion and ubiquitous RNases
• activation of innate immune nucleic acid sensors
• off-target effects: suppression of unintended homologous targets, activation of DNA repair pathways, translocations or imprecise gene editing