I currently study one protein, which is represented in two isoforms in human cells: wild-type transcript giving rise to the full length functional protein and truncated variant, lacking the entire exon N, due to alternative splicing event. The splicing leads to the introduction of premature stop-codon resulting in the functional dominant-negative truncated protein product.
Thinking on possible factors which can regulate the formation of truncated isoform, we asked whether it is known, if microRNAs, targeting particular exon, can interfere thereby with alternative splicing? An in silico search gave ca. 20 potential microRNAs binding within the exon N of my gene.
But before thinking about it further, I wanted to ask - maybe someone could help me with a couple of references on this topic (my PubMed search gave no relevant results) or someone has an experience with this phenomenon in the mammalian cells?
I don't think that miRs can effect directly on the splicing process (haven't seen any paper about it) since the maturity of the miR occur in the cytoplasm, and there for only the mature mRNA is available for it. there is a very interesting paper on the change in App splicing variants due to miR-124 expression, but it is a secondary effect.
The direct control of AS by miRNA is not yet known. The closest things that are known:
1) Indirect control of AS through the regulation of splicing factor mRNA expression by a define miRNA
2) Direct control of AS through snoRNA (Scott M NAR2012)
If one can demonstrate that a define miRNA can directly bind pre-mRNA and redirect splicing just as splice switching oligonucleotide does, that would open the door to a new mechanism of gene regulation, something that would most probably go very high in term of impact factor.
Go and good luck!
Thank you for your comment, JP!
There is one fantastic paper:
Control of alternative splicing through siRNA-mediated transcriptional gene silencing
Mariano Alló et al
Nature Structural & Molecular Biology 16, 717 - 724 (July 9, 2009)
where the authors actually could show that these two pathways - AS and RNAi - can crosstalk to each other. I thought this tool would be quickly implemented in the labs, but there were not many reports on that so far. But i think, if it works with exogenously added siRNA, there must be definitely an endogenous type of such a control existing.
In this case the exogeneous siRNA are targeting DNA and not pre-mRNA. It is intended to be recognized by AGO1 and subsequently lead to histone methylation and a more compact chromatin structure. The rational is that when you slow down polymerase (in instance by a more condensed DNA), you give the time to the alternative exon to be spliced effectively (more inclusion).
As for the occurance of this mechanism by endogenous miRNA? This I don
- Badges
- Science topic
- Similar topics
- Biological Science
- Biochemistry
- Biomolecules
- Nucleic Acids
- RNA
- Small RNA
- microRNA