The RNA world from whence we sprang strikes again, this time giving us a glimpse into its own internal dynamic. 18 months ago I wrote the following post — which will give you the background to follow the latest (found at the end after the (***)
Life is said to have originated in the RNA world. We all know about the big 3 important RNAs for the cell, mRNA, ribosomal RNA and transfer RNA. But just like the water, sewer, power and subway systems under Manhattan, there is another world down there in the cell which doesn’t much get talked about. These areRNAs, whose primary (and possibly only) function is to interact with other RNAs.
Start with microRNAs (of which we have at least 1,500 as of 12/12). Their function is to bind to messenger RNA (mRNA) and inhibit translation of the mRNA into protein. The effects aren’t huge, but they are a more subtle control of protein expression, than the degree of transcription of the gene.
Then there are ceRNAs (competitive endogenous RNAs) which have a large number of binding sites for microRNAs — humans have a variety of them all with horrible acronyms — HULC, PTCSC3 etc. etc. They act as sponges for microRNAs keeping them bound and quiet.
Then there are circular RNAs. They’d been missed until recently, because typical RNA sequencing methods isolate only RNAs with characteristic tails, and a circular RNA doesn’t have any. One such is called CiRS7/CDR1) which contain 70 binding sites for one particular microRNA (miR-7). They are unlike to be trivial. They are derived from 15% of actively transcribed genes. They ‘can be’ 10 times as numerous as linear RNAs (like mRNA and everything else) — probably because they are hard to degrade < Science vol. 340 pp. 440 – 441 ’17 >. So some of them are certainly RNA sponges — but all of them?
The latest, and most interesting class are the nonCoding RNAs found in viruses. Some of them function to attack cellular microRNAs and help the virus survive. Herpesvirus saimiri a gamma-herpes virus establishes latency in the T lymphocytes of New World primates, by expressing 7 small nuclear uracil-rich nonCoding RNAs (called HSURs). They associate with some microRNAs, and rather than blocking their function act as chaperones < Nature vol. 550 pp. 275 – 279 ’17 >. They HSURs also bind to some mRNAs inhibiting their function — they do this by helping miR-16 bind to their targets — so they are chaperones. So viral Sm-class RNAs may function as microRNA adaptors.
Do you think for one minute, that the cell isn’t doing something like this.
I have a tendency to think of RNAs as always binding to other RNAs by classic Watson Crick base pairing — this is wrong as a look at any transfer RNA structure will show. https://en.wikipedia.org/wiki/Transfer_RNA. Far more complicated structures may be involved, but we’ve barely started to look.
Then there are the pseudogenes, which may also have a function, which is to be transcribed and sop up microRNAs and other things — I’ve already written about this — https://luysii.wordpress.com/2010/07/14/junk-dna-that-isnt-and-why-chemistry-isnt-enough/. Breast cancer cells think one (PTEN1) is important enough to stop it from being transcribed, even though it can’t be translated into protein.
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[ Proc. Natl. Acad. Sci. vol. 116 pp. 7455 – 7464 ’19 ] The work reports a fascinating example of that early world in which the function of one denizen (a circular RNA called cPWWP2A) binds to another denizen of that world (microRNA 579 aka miR-579) acting as a sponge sopping up so it can’t bind to the mRNAs for angiopoetitin1, occludin and SIRT1.
So what you say? Well it may lead to a way to treat diabetic retinopathy. How did they find cPWWP2A? They used the Shanghai BIotechnology Company Mouse Circular RNA microArray which measures circular RNAs. They found that 400 or so that were upregulated in diabetic retinopathy and another 400 or so that were downregulated. cPWWP2A was on of the 3 top upregulated circular RNAs in diabetic retinopathy. cPWWP2A comes from (what else?) PWWP2A, a gene coding for a protein which specifically binds the histone protein H2A.Z.
Overexpression of cPWW2PA or inhibition of miR-579 improves retinal vascular dysfunction in experimental diabetes.
So here is all this stuff going on way down there in the RNA world, first interacting with other players in this world and eventually reaching up to the level we thought we knew about and controlling gene expression. It’s sort of like DOS (Disc Operating System) still being important in Windows.
How much more stuff like this is to be discovered controlling gene expression in us is anyone’s guess
Chemiotics II 