Why drug discovery is so hard: Reason #21 — RNA sequences won’t help you determine function

We are just beginning to understand all the things RNA does in the cell, despite its importance obvious to all for half a century (think messenger RNA which goes back that far).  This means that RNA is likely to be a target of useful drugs.  Posts #4, #11 and #20 concern some of the more newly discovered effects of RNA in the cell.

While we’re still discovering proteins with no obvious resemblance  in their amino acid sequence to known proteins, most of them do have some resemblance we’ve seen before.  So if we see a kinase-like domain, or a group of 7 rather hydrophobic sequences, we have a leg up on what that protein is actually doing.

A similar attack (comparing sequences to RNAs of known function) should help us figure out what some of the RNAs in the cell not coding for protein are actually doing.  If you see a mistyke in this sentence, you still probably know what I meant (e.g. how that word is meant to function in the sentence).  That’s the hope underlying the technique anyway

Recent work in the zebrafish [ Cell vol. 147 pp. 1537 – 1550 ’11 ] shows that this isn’t very likely in the RNA world. For some background on large intervening nonCoding RNAs (lincRNAs — aka lncRNAs) see https://luysii.wordpress.com/2011/03/02/we-dont-know-all-the-players-which-is-why-finding-good-drugs-is-so-hard/.  The zebrafish has become a plaything of embryologists (because it is transparent, and because like most fish (except sharks) it is a vertebrate.

At any rate the work found some 550 distinct lincRNAs in the zebrafish.  But only 29 had detectable sequence similarity with lincRNAs in mammals (which are just as numerous).  Even though chromosomes have been scrambled many times over geologic time, many genes near each other in the zebrafish are near each other in humans as well (the term for this is synteny).  This means one can look at DNA to see where the lincRNA is binding in two organisms, and infer that they’re doing something similar physiologically if they are binding to a syntenic site.

So they did this and found some  lincRNAs with almost no sequence similarity to each other binding to identical syntenic sites in man and zebrafish.  Next they used antisense reagents targeting the small regions of the lincRNAs conserved between us and fish and produced developmental defects (in the fish)  Amazingly, despite very little sequence similarity, human orthologs (determined by synteny) could prevent the embryological defects.

So in this case at least, and probably more generally, we’re not going to be able to look at the sequence of lincRNAs (or the many other types of non messenger RNAs present in the cell) and infer what they are doing.  This will make drug discovery in this area even harder.

 

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