RNA-targeting CRISPR reveals that noncoding RNAs are not 'junk'

Some non-protein coding DNA produces RNA which serves a purpose. We also know that there are large areas of non-coding DNA which are very important for transcriptional regulation.

But it remains true that there are large amounts of non-coding junk DNA which is under no selection pressure. It may be important for spacing out sections of DNA or it may just be along for the ride after being incorporated by ancient splicing errors or viruses. It's just frustrating to keep reading this articles about how, "it's not junk after all," when it has been known for decades that DNA/RNA have many non-coding functions and it has also been known for decades that there truly is "junk" DNA.

It seemed likely that the parts we don't understand likely served some purpose; assuming they were junk because we don't understand their function is like a user deleting random system files because they "don't use them."

That’s interesting, it’s like the difference between code used at runtime (protein coding DNA) and initialization code (lncRNAs). Both have to be there for the program to work, but the initialization code is only used at startup to look at the environment and set up flags and data structures for the rest of the code. There’s probably signaling pathways that interact with the lncRNA genes which are part of cell differentiation.

One would think by this stage of Science, when it comes to naturally occurring phenomena, there is only “yet to be understood” things and never “junk”.

For those who want to see a really fascinating argument that has lasted for a while, about junk DNA, functional selection, data, and models of evolution, start at http://cryptogenomicon.org/encode-says-what.html and then https://www.cell.com/current-biology/fulltext/S0960-9822%281... and https://www.nature.com/articles/d41586-024-00575-x (unfortunately paywalled).

From what I can tell, ENCODE project collected a ton of data suggesting that large regions of DNA which are not under functional selection (to the extent that we can measure that) are actively transcribed. They released some press and papers suggesting this meant that "junk DNA was not actually junk", which led Eddy to have a rage fit and propose an experiment to support his beliefs.

From what I can tell, we still don't have a great explanation for why large regions of DNA that are not under apparent functional selection are constantly being transcribed and what evolutionary impact that has on organisms. Personally I think Eddy greatly overplayed his claims, depending on some historical details in genome analysis that probably are dated and missing critical new biology, but honestly, these are areas where the theories and data are so ambigious, you can construct any number of narratives explaining the observed results.

Just like the "junk DNA" of the 1990's wasn't junk either.

We're just scratching the surface of the complexity encoded into DNA and RNA.

It's not the base pairs that are expressed, all the stuff not expressed is encoding information as well. DNA, like proteins, encodes information in the way it folds itself around histones. DNA can't be expressed if it's still in a compact state!

So it look like RNA is similar. The noncoding sections are part of the system that regulates how the encoding parts are encoded.

Could some junk be similar to commented out code? Features ready to be turned on if ever needed.

It seems like that would be a smart strategy for evolution instead of permantely deleting something.

How many possible combinations of RNA and DNA can there be?

Is it fewer then that due to what we know about variance in codon sequence alignment?

Does protein coding viability further limit the viable combinations?

lncRNA are very weird and I think they challenge some of the common, traditional assumptions about how cells work. Basically, the traditional view of RNA was that it's a messenger between the DNA and proteins. That is, it just functions a way to transfer genomic information to the protein factories (ribosomes). There were some widely known exceptions to this, like ribosomal RNA, which forms essential parts of the structure of ribosomes, so it's not just a messenger, it actually has a functional role in building a key cellular machine. My sense was that was viewed as a weird edge case that ribosome biologists were concerned with.

Anyways, there's been an explosion of different classes of RNA in the past decade or so. This has been driven by new techniques in RNA sequencing technology that allow us to detect and sequence RNA in a more unbiased and high-throughput way. What we saw was a huge number and variety of RNA molecules in cells that don't look like they encode any protein. So, this fundamentally breaks that assumption about RNA's role as "just" a messenger.

The best characterized class of these weird new non-coding RNA's is probably micro-RNA. They're very short stretches of non-protein-coding RNA, and it seems that they bind to other sequences of RNA and prevent their translation to proteins. So, RNA has at least one layer of self-regulation. Then we see long non-coding RNA. They can act as "sponges" or buffers of microRNA by preferentially binding to miRNA, preventing the micro-RNA's interaction with their normal protein coding RNA targets. So, there's another layer: long non-coding RNA buffers microRNA which inhibits translation of messenger RNA. Further the long RNA can also condensate into these structures that are similar to droplets of oil in water. They're transitory structures that form and dissolve then reform quickly and repeatedly. What they do is still a bit vaguely understood but they seem to bring together very weakly interacting proteins and RNA in concentrations that wouldn't be possible just by diffusion within the cell. So, there's another layer of regulation: long coding RNAs form condensates to that allow interactions between proteins that wouldn't happen otherwise.

All of this is complicated by the fact that these things have other weird properties. They aren't expressed very frequently, so they're hard to detect. They're not very well conserved evolutionarily, i.e. their sequences diverge rapidly between species. They don't really have fixed structures, they're more just like floppy, sticky noodles. This would typically indicate they're not functional or at least non-essential. How could this be important? It's an RNA that doesn't make a protein, isn't very abundant, has no defined shape, and evolution doesn't seem to care much about the details of its sequence.

*But*, as this paper shows, they're absolutely essential for cellular function. If you take them out of cells, the cells die.

So, all that to say that the idea of biology as working like a little computer; just a series of linear information transmission steps, is probably rather misleading in many cases. Instead it's a tangled mess of weak interactions that depends on subtle biochemical effects like condensation. It's noisy and imprecise at the molecular level, but all the self-interacting layers of regulation and interaction somehow give rise to remarkably precise and adaptive responses at the tissue and organismal level.

We know so little about DNA and RNA still, and yet we allow medical companies to make mRNA 'vaccines' that supposedly will working exactly as they say. How can that be possible when we don't even fully understand the system on which it is built?

It's like trying to repair a sinking ship at sea without understanding how the planks and caulking displace water. Sure you might patch it temporarily, and might even keep it afloat, but what other problems are you creating that you literally don't know anything about...

Quelle surprise.

who thought they were junk?

"You don't say..."

The article, unfortunately, repeats the 70-year debunked articulation of the "central dogma".

Sad.

https://en.m.wikipedia.org/wiki/Central_dogma_of_molecular_b...