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Enter GlycoRNAs

Layer upon layer! That’s what cell biology provides you with – just when you think you understand some area of it, things turn out to be more complex. I’m going on in this mode after looking over this new preprint from the Bertozzi lab at Stanford, which uncovers a new class of biomolecules that no one had seen before.

It’s been known for a long time that proteins are modified with glycan residues – it’s a major type of post-translational modification. Such groups are crucial for molecular recognition in protein-protein interactions in immunology, cellular adhesion, secretory pathways and more. But until now this sort of carbohydrate-chain labeling had never been known to intersect with the large, various, and equally vital world of RNA species. As for those, I’ve said many times that back in the 1980s no one would have believed the huge variety of RNAs that have turned out to be active species in the living cell. Short hairpin RNAs, double-stranded RNAs, long noncoding RNAs, circular RNAs, small nuclear RNAs and many others form a whole world of signaling and regulation that people used to be totally unaware of, and that story is nowhere near being fully written or (especially) fully understood. This new paper just underscores that.

This was a discovery enabled by a new method for analysis, an example of what Freeman Dyson and others have noted as a cycle of new phenomena being recognized once someone invents a technology that lets them finally be noticed. In this case, it’s yet another application of azide/alkyne click chemistry. Bertozzi’s lab has developed the use of azido-sugars that get incorporated into glycan side chains, and these can then be labeled by various alkyne-containing probes. (It’s getting to the point where it’s hard to remember chemical biology before this sort of labeling was available – you could make a solid case that it’s one of the fundamental enabling technologies that’s made the field what it is today). They’ve been using this method to track down all sorts of new information about the glycan world, but they noticed, to their surprise, that some of this click-labeling was apparently showing up in subcellular fractions that were thought to be almost entirely composed of RNA.

And so they are! It turns out that Y-RNAs (yet another of those weirdo little essential thingies) do in fact pick up glycan residues. Closer study shows that it’s the guanosines that get labeled, and this process seems to be general across a wide variety of cell types (and in different species). There are interesting differences in the abundance of the glycoRNAs, which of course are as yet unexplained, since we don’t know what they’re doing in there in the first place. The side chains have varying amounts of the different sialic acids in them as well, which also has to mean something. Known disruptors of protein glycosylation also affected the levels of glycoRNAs, suggesting that the same enzymes and pathways could be involved here as well. The glycoRNAs themselves seem to be associated with the membranes of various organelles – they’re not really found in the nucleus, for example.

Well, a new area of cell biology has opened up – not for the first time, and not for the last. Here’s the paper’s conclusion:

The framework in which glycobiology is presently understood excludes RNA as a substrate for N- glycosylation. Our discovery of glycoRNA suggest this is an incomplete view and points to a new axis of RNA glycobiology, including unprecedented enzymology, trafficking, and cell biology.

Absolutely. It’s anyone’s guess what these things are being used for and what diseases might be associated with dysfunction of their pathways. Whenever something like this happens, I think about how many other things are still out there like this that we haven’t come across yet, and what that means for our attempts to understand cell biology in general. Using deep learning and so on to derive connections in our existing knowledge is a perfectly reasonable idea, but it has to be remembered that the reasonably well-known and patterned landscape of our biology knowledge is embedded in a much larger territory of ignorance. There are mountains, lakes, and canyons out there that we know nothing of, and we are unlikely to find them by rearranging the data we already have. This paper serves as an example of finding something new, and there are still so many new things to find. . .

30 comments on “Enter GlycoRNAs”

  1. was NHR_GUY says:

    ” you could make a solid case that it’s one of the fundamental enabling technologies that’s made the field what it is today” – read Nobel Prize *wink wink*

    1. anon says:

      I’ve met some people who say click hasn’t actually led to any real biological discovery. Bio snobs…

      1. Anon says:

        They just be out of their minds. You can say it for Fullerenes and rotaxanes though. They led to nothing.

  2. Mister B. says:

    I just want to mention that to the best of my knowledge, this is the first time you write an article about a preprint ! It is great as we can all access it ! Open Access science !

    And definitely, a great publication too even if I may partially understand its impact ! Thanks Derek !

    1. Derek Lowe says:

      Oh, I’ve done several, off both BioRxiv and ChemRxiv – I agree, it’s great for everyone to be able to see the papers!

      1. Mister B. says:

        Sorry for my mistake ! I will pay more attention to your sources !

        1. Derek Lowe says:

          No problem! Just wanted to let you know that I agree that your point is a really good one. . .

  3. Mole says:

    Are these mountains? Or are ultra sensitive tools enabling the discovery of molehills of limited function and penetrance?

  4. Farmer says:

    “….huge variety of RNAs that have turned out to be active species in the living cell. Short hairpin RNAs, double-stranded RNAs, long noncoding RNAs, circular RNAs, small nuclear RNAs and many others….”

    Seems we are still in an RNA world after all.

    1. ScientistSailor says:

      sounds like the start of a Weird Al spoof of a Madonna song…

  5. JB says:

    Really cool stuff! This opens up a giant can of new worms for how RNA levels may be regulated. Also, glycans can significantly affect the chemistry of biomolecules they’re attached to. Would a big modification like a glycan affect how well PCR preps work? Are we missing a big fraction of RNAs that may be glyco modified when doing expression analyses?

  6. Glycan Boy says:

    My immediate reaction to something so novel is that it could be due to contamination, and in this case, the contaminant could be N-glycosylated peptides. Although the paper claims that the “glycan-RNA linkage was not sensitive to stringent protocols to separate RNA from lipids and proteins including organic phase separation, proteinase K treatment and silica-based RNA
    purification”, they did not directly address this obvious issue by providing explicit evidence for lack of contamination from multiple, orthogonal, fit for purpose methods. Maybe they will when it’s actually published, but if I were the reviewer, this would be the major issue that has to be addressed.

  7. Greg says:

    It is an interesting aside that you make about deep learning. However, I think it is applicable to all learning – artificial or biological. Both biologists and models have to be quite careful when they go into mechanistic reasoning since there is so much we don’t know!

    Models of the ODE, mechanism based variety are the ones that are the most problematic here

  8. mfp says:

    Is there evidence to show that the RNA glycosylation event occur pre cell-lysis?

    1. Me says:

      ^^^That^^^

  9. anon says:

    “There are mountains, lakes, and canyons out there that we know nothing of…” reference please Derek? It seems equally likely there are molehills that may look like mountains on first inspection due to increasingly sensitive analytical detection tools. A key question we face as scientists will be how to differentiate these. Penetrance and function seem like excellent starting points.

    1. Derek Lowe says:

      We didn’t know about any of the other RNA species mentioned, or about phase-separated condensates, or about internal ribosome entry sites, or about prions, or about the neurotransmitter activity of things like CO or H2S, or the possibility of induced pluripotent stem cells, or about alternate cellular death pathways like necroptosis, or about enhancers/superenhancers of transcription, or about nonstructured complexes of disordered proteins, or. . . .

      1. anon says:

        Touche. And I hope you are right. I am just saying it may be a bit early to conflate glycoRNA with those discoveries. I will be excited to see what follows the “fascinating observation” stage.

        1. Derek Lowe says:

          True! It’s going to be exciting to watch. . .

  10. Cvb says:

    GlycoDNA is already known wuite some time: Borst P., 1993 β-D-glucosyl-hydroxymethyluracil: a novel modified base present in the DNA of the parasitic protozoan Trypanosoma brucei. Cell,75: 1129-1136.

    1. JB says:

      Eh, but it’s not a nucleic acid modified by an entire glycan like what is described here. The findings in the paper here imply a large amount of unknown cell physiology ripe for exploring now – somehow rRNAs can get into the entire ER to Golgi transit system and are recognized by glycotransferases. En bloc transfer of the N-linked precursor in the ER also isn’t limited to peptides it seems. Tons of details need to be filled in here, and it’ll be interesting to see how this changes with disease.

      1. Jb says:

        Typo….only meant RNAs, not ribosomal RNAs

  11. gippgig says:

    Has anyone looked for modifications to the phosphates in nucleic acids? I strongly suspect there are phosphotriesters out there regulating genes & even more exotic things such as replacement of an individual phosphate with a sulfate, silicate, carbonate, borate, acetal/ketal, … are possibilities.

    1. Curt F. says:

      At least one naturally occuring phosphate modification is known. Phosphorothioates, long used by chemists as an artificial modification to synthetically produced oligonucleotides, were later found to be naturally occurring in certain bacterial genomes. In 2005 some folks found an operon that sensitized the host genome to degradation during electrophoresis (10.1111/j.1365-2958.2005.04764.x) and showed that it involved sulfur incorporation into the DNA. Later analyses (10.1038/nchembio.2007.39) showed that this incorporation was a sequence-specific and stereoselective incorporation of sulfur into non-bridging oxygen atom of the phosphate group. Bacteria are believed to do this self-modification in order to be able to better detect and degrade foreign DNA (e.g. from phages) when it comes their way.

  12. Klagenfurt says:

    Uh huh. Don’t forget arsenate esters.

    1. Anonymous says:

      “Uh huh. Don’t forget arsenate esters.” For those who may not know the reference:
      https://en.wikipedia.org/wiki/GFAJ-1 . GFAJ-1 was a microbe ALLEGED to be able to incorporate arsenate into its DNA in place of phosphate.

    2. Wavefunction says:

      Glyco RNA is far more plausible than the chemically unstable arseno DNA.

    3. Hap says:

      Arsenates had the problems of not really being stable enough to exist under biologically relevant conditions, so a paper postulating that they were genetic material had to show that they were able to be stabilized under relevant conditions and that they actually were present. Hence arsenic DNA had a much bigger barrier to credibility to surmount than glycated RNA does. (Bertozzi’s status and previous record probably also come to play in how much people are willing to trust the result).

      1. loupgarous says:

        According to <a href=" an article by the Arizona-based physicist and director of Director of ASU's "BEYOND: Center for Fundamental Concepts in Science", ."GFAJ" in "GFAJ-1" stands for "Give Felisa a Job", specifically, Felisa Wolfe-Simon, main author of the paper describing the organism whose DNA contained arsenates where phosphates usually exist.

        Davies explains:

        “I fell into a role as Felisa’s unofficial mentor and encouraged her to stick to her guns. In this, I had the advantage of being unencumbered by knowledge. I dropped chemistry at the age of 16, and all I knew about arsenic came from Agatha Christie novels. But who was going to fund the search for arsenic life? We applied to a philanthropic organization but got rejected. “Too speculative,” we were told. Then NASA came to the rescue. They were prepared to give it a try, so after a brief spell at Harvard, Felisa took yet another insecure position, at the U.S. Geological Survey in California, where she began working with Ron Oremland. Together they began trawling Mono Lake, near Yosemite National Park, in search of evidence.

        Meanwhile, Felisa, Ariel Anbar and I set out the case for arsenic life in a short paper, which we struggled to get published. Typical of the response was the wry comment of a prominent British astrobiologist after I presented our case at a Royal Society meeting in London last January: “You’d be off your trolley to go searching for arsenic-based life.”

        By then Felisa already had in her laboratory the bacteria that were to make her famous. It took months of painstaking work to assemble a convincing case that GFAJ really had incorporated arsenic into its vital innards. At every step, the experimental results might have shot down her big idea, spelling the probable end of a promising scientific career. But when I went to see GFAJ for myself last April, Felisa’s eyes were aglow with excitement—it was all coming together far better than she had dared to hope.

        Now that she is in the glare of world attention, I have little doubt that someone will indeed “Give Felisa a Job.”

        The last position mentioned in Wolfe-Simon’s CV is as Chan-Norris Distinguished Visiting Professor at Mills College, and a number of other gigs “schedule permitting”, though she’s published one interesting paper since the GFAJ-1 episode,,

        J.B. Glass, A.T. Poret-Peterson, Felisa Wolfe-Simon and A.D. Anbar (2013). Molybdenum limitation induces expression of the molybdate-binding protein Mop in a freshwater nitrogen-fixing cyanobacterium. Advances in Microbiology. 3(6A): 9-15.

        So, she landed on her feet afterward.

  13. MTK says:

    Hhhmmm.

    I’m not surprised to see this only because it seems that post-translational modifications observed in epigenomics seems to crop up in epitranscriptomics also. (Not an expert, so I’m not sure how true that statement really is, just my outside observation.) Much like with RNA methylation, there’s a reasonable chance that readers, writers, and erasers of RNA glycosylation will be found pointing to some functional importance.

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