How about some cool science as we head toward the weekend?
Let’s talk about long noncoding RNAs (lncRNA) – they are (somewhat arbitrarily) defined as stretches of DNA that are at least 200 base pairs in length that are transcribed into mRNA but have little potential to code for proteins. Determining the function (if one exists) of a particular lncRNA can often be difficult. In part, this may be due to the fact that lncRNA evolve much more quickly than protein-coding genes do and therefore exhibit a much smaller degree of sequence conservation, which can make identifying orthologs in other related organisms more difficult. Nevertheless, if a particular lncRNA is functionally important, we would usually expect to see copies of it in related organisms, so finding these homologs can be an important indicator of function.
A new paper in Genes and Development by Quinn et al. is a useful demonstration of this. The authors find evidence of 47 homologs of roX, an lncRNA involved in X chromosome dosage compensation, across 35 fruit fly species. The researchers identity roX homologs based on a combination of short regions of sequence conservation (“microhomology”), RNA secondary structure and synteny (i.e., similarity in location along a chromosome) Here is the abstract (I believe the paper itself is open access):
Many long noncoding RNAs (lncRNAs) can regulate chromatin states, but the evolutionary origin and dynamics driving lncRNA–genome interactions are unclear. We adapted an integrative strategy that identifies lncRNA orthologs in different species despite limited sequence similarity, which is applicable to mammalian and insect lncRNAs. Analysis of the roX lncRNAs, which are essential for dosage compensation of the single X chromosome in Drosophila males, revealed 47 new roX orthologs in diverse Drosophilid species across ∼40 million years of evolution. Genetic rescue by roX orthologs and engineered synthetic lncRNAs showed that altering the number of focal, repetitive RNA structures determines roX ortholog function. Genomic occupancy maps of roX RNAs in four species revealed conserved targeting of X chromosome neighborhoods but rapid turnover of individual binding sites. Many new roX-binding sites evolved from DNA encoding a pre-existing RNA splicing signal, effectively linking dosage compensation to transcribed genes. Thus, dynamic change in lncRNAs and their genomic targets underlies conserved and essential lncRNA–genome interactions.
I think it’s a neat demonstration of both the challenges and utility of using evolutionary conservation to help inform inferences regarding the functionality of non-coding genes. As we continue to get a better grasp of which non-coding sequences are important and which ones are less so, I expect to see many more studies like this.
Carl Zimmer also has an excellent write up of the paper here, which was the original inspiration for this post. Enjoy!
Edited to correct the number of species in which roX was detected.
… as I already mentioned: I am in definitely over my head!
Before taking my leave… I am becoming more and more impressed with the history of the imperial old guard of geneticists such as Mark Ptashne.
It would appear all of Molecular Biology is but a footnote to the efforts of the CSH Phage Group!
Check out these two links:
“Microbial Epigenetics Workshop”?! … who would of thought!? Hmmm – just the same, it would appear that the up and coming youngsters should be heeding more the classical papers authored by their predecessors, if Mark Ptashne is to be given his due.
One interesting wrinkle when it comes to epigenetic silencing of TEs is that there is often a cost involved with silencing when the TE has inserted itself near a gene. See Hollister and Gaut (2009) for a neat example:
Thanks for the comment on methylation marks. I’m not a biologist, but I am writing a review article for engineers interested in cross disciplinary topics (It’s going to be a 4 rate review article since I’m no specialist, but for the sort of venue I’m writing it’s hopefully educational), and I’m trying to assert an analogy between methylation marks and histone modifications as memory, in fact I call epigenetic marks a form of RAM.
Ptashne doesn’t like calling epigenetics a form of memory, but it looks to me like memory. Would you feel uncomfortable with the analogy of epigenetic marks and computer Random Access Memory.
I’ll try not to derail Dave Carlson’s OP and I’ll try to limit my discussion of this, but the question about “Epigenetics is like Random Access Memory” is vital to a paper I’m writing. If the discussion gets long, I’ll move it elsewhere.
Why not negative (purifying) selection?
Into the mix we’d have to add those species (eg muntjac) that seem to undergo more rapid rearrangements than our relatives. There may be a genomic distinction that causes fewer rearrangements in us, or selection against them which does not operate in muntjac, but it could simply be stochastic as well.
Interesting picture of the interphase chromosome BTW.
WHOA!!!! Studly find. This was worth the price of admission. Thanks. I’ll may reference this stuff in my review. 🙂
I may have to publish in Vixra, but I’m writing it partly for my own education.
Does that education include any geology or genetics or human population growth that you’re patently ignoring on your other “Black Swan” thread?
You didn’t ask me, but I would. I do have a foot in both camps, the informatic and the molecular biological, and I say ‘nah’. Same with ‘code’ 😉 Analogies are like bananas with an umbrella stuck in them, except when they are more like invisible battleships …
They are OK for illustration, but people can readily understand the actual thing. Analogies have a tendency to lead people astray, by over-egging the similarities and forgetting there must be differences too.
Analogies mislead. It’s the map/territory problem.
Something I learned from one of the NIH researchers today on micro RNAs that I think has relevance to the lncRNAs. There is a lot of redundcany with the micro RNAs and their gene regulation is mostly tuning, and it’s not unusual for 9 micro RNAs to be involved in the regulation of one protein. You knock out one, there isn’t much noticeable phenotypic effect. You knock out all 9, it’s lethal!
One paper was suggested as a resource:
DICER was mentioned as well in connection with microRNAs, and I found this one on my own:
Though miRNAs are totally at the opposite pole (so to speak) in length with lncRNAs. These RNA discoveries are happening at an explosive pace.
It seems some miRNAs proceed form lncRNAs so there is relevance there.
But there is this discovery reported this year:
Btw, Cold Spring Harbor — they harbor some top talent! I’ve always been impressed by the research that comes out of that place.
Alright some more lncRNA stuff fresh from my 1st two days of class in the NIH. 🙂
The term epigenetic has been evolving. It usually means methylation marks and histone modificaiton, but some will also include non-coding RNAs!
Something to be aware of is that some cells can duplicate without DNA! For example beginning with this paper in 1966:
It became apparent fertilized eggs could develop to the blastula stage (a few thousand cells) with no DNA in the nucleus, just left over mRNAs.
So, at least for somatic cell lines, there is likely some transgenerational RNAs following mitotic divisions. It is thus arguable an “epigenetic” mark.
I would not be surprised if the non-coding RNAs are performing some sort of monitoring and surveillance between mitotic divisions. There is short-term intergenerational information being stored there and we don’t realize it!!
The lncRNA is involved with the PRC2 polycomb complex which modifies histones and histones signal chromatin accessibility and chromatin accessibility affect gene expression. Wew!
These are the more technical details:
Uhmmm… I think you are misreading Ptashne.
Epigenetics implies by definition “memory” of sorts. Ptashne merely remarks that nucleosome modification be it DNA methylation or Histone acetylation plays a role in down regulating gene expression but plays no role in propagating “memory”. Memory propagation is done by transcription factors. I advise you to read the last few paragraphs of his letter.
Your analogy about bananas was delicious! … metaphorically speaking! 😉
Hi again Allan… btw I quoted you on the AP Biology teachers’ forum to which you do have access.
Regarding chromosome architecture and its importance… I think it important! If so – it stands to reason that whatever contributes to chromosome architecture would be important even if redundant and even if commonalities across lineages represents convergent evolution. i.e. the TEs being tamed and subsequently then co-opted need not be identical from lineage to lineage.
but we rehash…
I think the RNAs have something to say. 🙂 If by memory propagation we also mean memory propagated during mitotic division, I think the RNAs play a role.
A sneak behind he paywall, notice ncRNAs mentioned.
Help me out here Allan… Not just protein, but RNA can also play the role of “transcription factor”? True or False
I was going by the wiki definition. Am I mistaken to use it? Is there another convention?
I’m not a biologist.
Sure, chromosome architecture is important, but I suspect it is quite plastic nonetheless. You see a lot of to-ing and fro-ing between acrocentric and metacentric chromosomes in mammals depending on the polarity of female meiosis, and without some level of plasticity, we’d be struggling to account for karyotype differences between species more generally.
And you could not have selection for linkage disequilibrium if loci could not shift, potentially influencing regions of chromatin control.
I’m no expert, but I’d say ‘true’. But the convention does appear to be to say they are proteins, and nucleic acid regulators are therefore something else! As an RNA-World-er, I’d say nucleic acids must have taken the role initially.
PIWI seems to regulate lncRNAs. If lncRNAs are regulated, it really suggests to me they have function!
It’s those guys at Cold Spring Harbor again. Man they’re good.
Here’s a big daddy repetitive lncRNA that’s megabases long and repeats a 359 bp long theme. They found a function for this behemoth.
The following is my instructors’ suggested supplemental reading for lncRNAs this week. My class is mostly 75% focused on miRNAs, but since they have relation to lncRNAs, the lncRNAs were covered this week in class.
lncRNAs are kind of a funny classification. The 200 bp limit is a bit of an accident as the company who found them arbitrarily assigned the number. There are lncRNAs that may be shorter. Also, lncRNAs are sort of a miscellaneous category right now, so they aren’t well defined.
I was surprised that introns, pseudogenes, alternative spliced exons can generate lncRNAs — so the classification is a bit of a hodge podge right now.
Anyway here is the suggested reading list:
WEEK 2. Long Non-Coding RNAs: Biology and Functions
1. Quinn JJ, Chang HY. (2015). “Unique features of long non-coding RNA biogenesis and function.” Nat Rev Genet. 17(1):47-62.
2. Raveh E, et al. (2015). “The H19 Long non-coding RNA in cancer initiation, progression and metastasis – a proposed unifying theory.” Mol Cancer. 14(1): 184
3. Hezroni H, et al. (2015). “Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species.” Cell Rep. 11(7): 1110-22.
4. Hung CL, et al. (2014). “A long noncoding RNA connects c-Myc to tumor metabolism.” Proc Natl Acad Sci U S A. 111(52): 18697-702.
5. Liu YR, et al. (2015). “Long noncoding RNAs in hepatocellular carcinoma: Novel insights into their mechanism.” World J Hepatol. 7(28): 2781-91.
6. Sigdel KR, et al. (2015). “The Emerging Functions of Long Noncoding RNA in Immune Cells: Autoimmune Diseases.” J Immunol Res. 2015: 848790.
Thanks for the references, Sal. I have a rather overwhelming number of other things to do at the moment, but I will try to check these out when I have some more time.
Hey, I totally understand now that my semester is finally in swing.
Good luck with your stuff too!
This is one of the frontier papers of lncRNAs even though it was written in 2012. It’s behind a paywall, but I’ll give you the abstract:
Epigenetic Regulation by Long Noncoding RNAs
Jeannie T. Lee
It was a very enlightening read. It echoes the sympathies of the NIH researchers.
This is a free article. You can get the PDF from this link: