Non-coding lncRNAs 2 Flashcards
What is the main known function of a growing number of lncRNAs?
Gene regulation
lncRNA transcription can affect genes on the same chromosome …
while the actual lncRNA molecule has no effect
How can lncRNA effect neighbouring genes?
Increase accessibility of DNA regulatory elements (e.g. enhancers) in chromatin
Block neighbouring gene expression (transcriptional interference)
What mediates transcript dependent modes of lncRNA gene regulation?
The RNA molecule produced
What are the functions of nuclear lncRNA transcripts?
Act at site of expression + distant location in nucleus
What are the functions of cytoplasmic lncRNAs?
Function post-transcriptionally
Name an example of lncRNAs that accumulate at their site of synthesis + act in cis in the nucleus
H19 (gene imprinting)
EMICERI (dev. of drug resistance in melanoma)
PVT1 regulation of c-MYC oncogene (multiple cancers)
Name an example of lncRNAs that move away from site of synthesis + act in trans (regulate genes on other chromosomes)
HOTAIR (breast cancer metastasis)
Paupar (neuroblastoma)
Name the 3 basic mechanisms of actions of transcript dependent lncRNA gene regulation
Scaffold
= acts as platform which other molecular components can assemble
Decoy
= Bind to target molecules to titrate them away
Guide
= Guide regulatory complexes to their site of action
Name an example of a lncRNA that acts as a scaffold
HOTAIR lncRNA co-ordinately binds PRC2 + LSD1 in the nucleus
-> targets them to sites on chromatin
Name an example of a nuclear lncRNA that acts as a decoy
PANDA binds + sequesters NF-YA transcription factor in the nucleus
How do guide lncRNAs recognise + bind to genomic binding sites?
Directly
= base pair w/ complementary DNA in a sequence specific manner -> forms RNA-DNA-DNA triplex
= through specific lncRNA-RNA interactions at transcribed genes
Indirectly
= via association w/ a transcription factor
How can cytoplasmic lncRNAs regulate gene expression post-transcriptionally?
Regulating mRNA stability
Modulating levels of mRNA translation
Competing for the binding of shared microRNAs (decoy)
Name an example of lncRNA that acts as a guide + forms a lncRNA-DNA-DNA triplex in cancer cells
MIR100HG binds to p27 (CDK1B) gene promoter + silences it
- > proliferation of triple-negative breast cancer (TNBC) cells
- > low survival
Name an example of cytoplasmic lncRNA that acts as a decoy
PTENP1 = PTEN pseudogene
Similar to PTEN tumour suppressor gene
PTENP1 = rich in cytoplasm
- > PTENP1 completes w/ PTEN mRNA for binding to miRNAs
- > PTEN is not down regulated by miRNAs
PTENP1 = often deleted in melanoma
What are the 2 possible ways to interfere w/ function of cancer causing lncRNA oncogenes?
Silencing lncRNA expression
Disruption of lncRNA function
How do you silence lncRNA expression?
Transcript degradation = by siRNAs (in cytoplasm) -> 19-22 nts long -> associate w/ RNA-induced silencing complex (RISC) -> guided to target lncRNA -> Ago2 cleaves lncRNA
= by anti-sense oligonucleotides (ASOs) (in nucleus)
- > 12-25 nts long
- > bind to lncRNA (base pairing)
- > recruits RNase H1 which cleaves lncRNA
What are the 2 advantages of nucleic acid based drugs as cancer therapies?
Selectively target any unique region of human transcriptome
Provide ability to target the “undraggable” portions of genome
What are the 2 problems of nucleic acid based drugs as cancer therapies?
Delivery
= how to get molecules to right location of the body
Designing oligonucleotides w/ minimal to no off-target effects or toxicity
How do you disrupt lncRNA function?
Use anti-sense oligonucleotides (ASOs) or small molecules to block lncRNA interaction w/ miRNA
