Let’s confuse ourselves thoroughly and talk about long noncoding RNA. It’s just part of the menagerie of RNA species that have come to light over the last twenty years, of course, and honestly you can confuse yourself with any of them. But just asking “what are lncRNAs doing?” is enough right there.
They’re lengthy stretches (>200 bases, as an arbitrary cutoff) of RNA that don’t seem to be associated with any particular gene, but are nonetheless transcribed and turned loose to float around. If you look closely, you can find a great number of these things (on the order of tens of thousands) inside cells. The assumption is that they have to be doing something, but what? They tend to be rather cell-type specific, and even cell-cycle or developmental-stage specific, which definitely argues for their utility. They don’t seem to be translated into protein, but even that is the subject of argument, with some groups saying that there are so-called noncoding RNAs that have been misannotated, and other proposals that they’re somehow translated into short-lived peptides that are difficult to detect. But it’s for sure that many of these things don’t look like they have open reading frames in them.
Are they conserved? More arguing. My understanding is that at a sequence level, they do seem to be more so than just a bunch of random RNA, for sure – people have seen what looks like conservation across species, for example. But it’s been hard to show that these variants are doing the same thing (whatever that may be) because the levels of the different transcripts vary so much (you’d think that a conserved type would show up in roughly the same amounts, but that doesn’t seem to be the case).
And as for relevance to disease, prepare yourself if you do a search: there’s an absolute firehose of literature on possible connections to cardiovascular disease, various tumor types, CNS conditions, developmental pathways of all kinds, and pretty much everything else you can think of. That’s what having no well-defined mechanism will do for you – lncRNAs are a blank screen on which you can draw most anything. Effects on mRNAs, on oligonucleotide stability or localization, on chromatin or the assembly of transcriptional machinery – sure, whatever. And the number of papers is growing steadily with no sign of leveling off. I would very much want to avoid having to bring order to even a small part of the literature in this area – there are so many reports, some of them describing the same RNA with different names, and some of them describing, no doubt, slightly different ones with the same name. As those links above show, there are a lot of ways to analyze and detect these things, and that scrambles the interpretation pretty well, too. From what I can see, it is truly a wild and lawless frontier.
Then you read a paper like this new one. The authors selected 25 lncRNAs in zebrafish, trying to pick ones that would be as functional as possible (previously proposed function, conserved sequence, high expression, position next to important DNA sequences, etc.) Then they used CRISPR to take them out. And guess what? Hardly anything happened. The resulting mutants were all viable, developed normally, and were fertile with normal offspring. A close look showed that some of the deletion mutants had slightly altered gene expression profiles for nearby sequences, and even those had no detectable phenotype.
So what does this mean? The authors say “LncRNAs might have redundant, subtle, or context-dependent roles, but extrapolation from our results suggests that the majority of individual zebrafish lncRNAs are dispensable for embryogenesis, viability and fertility“. It’s hard to argue with that, unless they managed to pick 25 loser sequences somehow. It could be that while they’re functional, they’re easily compensated for by other lncRNA species during development, which if true has implications for a lot of the hypotheses about their roles in the cell. It could be that in some disease states the roles of particular lncRNAs become much more defined – or not. As I said, the wild frontier. Welcome to it!