What are lncRNAs?

Many genes encode proteins and many other genes specify functional RNAs that do not encode proteins. The "RNA genes" include the classic genes for ribosomal RNAs and tRNAs as well as genes for very well-studied RNAs that carry out catalytic roles in the cell. There are a myriad of small RNAs required for things like splicing and regulation. All species, both prokaryotes and eukaryotes, contain genes for a wide variety or functional RNAs.

Eukaryotes seem to have an abundance of genes for small RNAs that perform a number of specific roles in regulation etc. They also have a lot of DNA regions complementary to long noncoding RNAs or lncRNAs (also lincRNA). The definition of long noncoding RNAs seems arbitrary and ambiguous [see Long Noncoding RNA]. Some of them might even encode proteins!

As a general rule, these RNAs are longer than 200 bp and some scientists put the cutoff at 1000 bp. Simple eukaryotes, such as yeast, don't have a lot of lncRNAs but eukaryotes with large complex genomes that are full of junk DNA seem to have a lot of different lncRNAs. The DNA regions¹ that specify these lncRNAs ar not conserved. This strongly suggest that many of the lncRNAs are spurious nonfunctional transcripts even though some of them have well-characteized functions [see On the function of lincRNAs].

As usual, we have a definition problem. Are "lncRNAs" just a generic class of long noncoding RNAs that include thousands of nonfunctional molecules that are nothing more than junk RNA? Or, does the term "lncRNA" refer only to the subset that has a function? If it's the latter, then we should probably be referring to "putative" lncRNAs most of the time since the vast majority have not been shown to have a function. (There are about 10,000 of these RNAs in humans.)

I don't see how you can avoid the elephant in the room whenever you talk about lncRNAs. The most important question in NOT whether some of them have a function—that was demonstrated 30 years ago. The important question is whether the majority, or even a substantial minority, have a function.

That's why I was eager to read a short review by Rinn and Guttman in a recent issue of Science (Rinn and Guttman, 2014). They describe two lncRNAs that probably play a role in organizing chromatin within the nucleus (Xist and Neat1, both fram mammals). That's cool.

Then they say,

Collectively, these studies suggest that lncRNAs may shape nuclear organization by using the spatial proximity of their transcription locus as a means to target preexisting local neighborhoods. lncRNAs can in turn modify and reshape the organization of these local neighborhoods to establish new nuclear domains by interacting with various protein complexes, including chromatin regulators. Once established, a lncRNA can act to maintain these nuclear domains through active transcription and recruitment of interacting proteins to these domains. While the mechanism for how lncRNAs establish these domains is not fully understood, it is becoming increasingly clear that lncRNAs are important at all levels of nuclear organization—exploiting, driving, and maintaining nuclear compartmentalization.

It sure sounds like they are describing a particular function (nuclear organization) to the majority of lncRNAs. But what if 90% of all 10,000 lncRNAs have no function and what if only 100 of the remaining functional lncRNAs are involved in nuclear organization? That means there are 900 functional lncRNAs that play a different role in the cell?

If that were true, you would write that last paragraph very differently. If you recognize the elephant, you might say something like this ....

Very few lncRNAs have been shown to have a function and there's a very good chance that most of them are spurious transcripts that have no function. However, a small percentage do seem to have a function. In this review we have identified some long noncoding RNAs that appear to be involved in nuclear organization. We propose to call these RNAs "noRNAs" for "nuclear organizer RNAs" on the grounds that once a function has been identified we should stop referring to them as lncRNAs.

But that doesn't sound nearly as exciting as the subtitle of the article, "Long noncoding RNAs may function as organizing factors that shape the cell nucleus" or the quotation that's prominently displayed in a box in the center of the page, "... it is becoming increasingly clear that IncRNAs are important in all levels of nuclear organization—exploiting, driving, and maintaining nuclear compartmentalization." When did science become so dedicated to hype over substance? I must have missed the memo.

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1. I use "DNA regions" instead of "genes" because the definition of a gene requires that the gene product be functional. You can't call them genes unless you have demonstrated that the RNA has a function.

Rinn, J. and Guttman, M. (2014) RNA and dynamic nuclear organization. Science 345"1240-1241 [doi: 10.1126/science.1252966]