There has been much discussion, here and elsewhere, on ‘epigenetics’, broadly understood as the control of gene expression. People who cling to ‘classical’ models are portrayed, by revolutionaries and their cheerleaders, as dinosaurs standing in the way of progress.
I could perhaps explain, to any interested bystander, my own rationale for my position, since I’ve requested that of others.
Those of us taught molecular biology between the 1960’s and the noughties assimilated a model of gene regulation that started with the classic work of Jacob and Monod on the lac operon.
The structural genes – the parts coding for actual protein, by transcription into mRNA and translation – are flanked by regions to which transcription factors bind. Transcription proceeds in one direction only (a DNA strand has 2 directions due to the asymmetry of the ribose links). ‘Upstream’ of the protein regions, factors (proteins or RNAs) bind and block or promote the activity of transcription enzymes. In the case of lac, binding represses. So if there is no lactose, the enzymes are not produced. Lactose causes the disassociation of the repressor and the enzymes for its metabolism are produced. Neat, huh?
Now, the classical operon is a prokaryotic feature. Prokaryotes have no histones, and they appear to lack DNA methylation mechanisms, so there can be no involvement of these extra layers. Analogies to ‘memory’ are rather strained. The bound lac repressor is a ‘memory’ the way someone hanging on to one’s ankles is a memory of that person!
Modern eukaryotes spool their genomes on histones. This causes an extra problem/opportunity, beyond basic DNA management, in getting transcription turned on or off. If there is no transcription to do, the DNA is tightly wound on the spools, which involves their methylation (methyl groups are hydrophobic, so cause tightening in the presence of water). If transcription is required, conversely, the methyl groups need removing, and further relaxation can be provided by acetylation. And what causes these changes? Ultimately, it’s those transcription factors. Extra elements are introduced into the cascade, but basically the same kind of promoter/repressor system as in prokaryotes initiates the extra work that needs to be done to expose the reading frame to transcription.
DNA methylation again causes the helix to tighten. One sees something very similar in the thymine-uridine distinction between DNA and RNA. Thymine has exactly the same molecular relation to uridine as methylcytosine has to cytosine, the difference being that thymine’s methyl group is permanent and not neighbour-dependent. A-T base pairs in double-stranded DNA cause the helix to be more tightly wound than dsRNA; methylated cytosines means that C-G pairs reinforce this effect, but reversibly.
These mechanisms provide an additional means of control compared to prokarotes – but the much stronger claim is that they are a separate means of control – that control is by such modification instead of transcription factor binding.
Now if, parallel to all this, one buys the notion that evolution happens, and that eukaryotes derive from prokaryotes, then clearly the basic system would be expected to be one of promoter/repressor binding, subsequently amended to extend to histone modifications and the additional, novel (and by no means universal) mechanism of DNA methylation. It seems unlikely that a completely separate system of regulation would arise driven by histone changes, when histone changes must occur anyway.
If, conversely, one thinks evolution does not happen, and one is further seduced by superficial resemblance and analogy, the idea that the histone and DNA changes constitute a separate level of control seems to hold considerable appeal. There’s no problem with a Designer choosing one mechanism in prokaryotes and another in euks. But the inconvenient fact is that the cascade, as far as has been elucidated, starts with TFs. So had Mukherjee given more (and appropriate) weight to transcription factors, he would pretty much have been writing an article on 60 year old molecular biology. Instead, he’s describing a revolution that hasn’t happened yet.
Histone/DNA methylation codes are not impossible, they just seem very unlikely to people with a particular background. One can invoke old saws about Kuhn, and revolutions proceeding death by death, but one also needs hard data.
That’s really helpful, Allan–not only because of the bio material, but on why the issue is so charged. Casts a few flecks of light into my general confusion. Really appreciate it.
Very well put, Allan.
The irony is that I am somewhat less of a “dinosaur” than you and Ptashne are. Thanks to my background in yeast silencing, I reckoned that ‘higher order chromatin structure’ can, in some cases, achieve primacy over TFs. Hence my surprise at Mark’s statement “And there is no evidence that coiling and uncoiling of DNA has a causal effect on gene activity.”
What to do? Well, to support my disbelief, I went looking for a solid counter-example. [Woo-meisters such as Sal need to take very careful note of the process involved here]. Lo and behold, I discover that the dinosaurs have the data on their side.
I do enjoy the spectacularly selective appeals to authority that the woo-meisters invoke: someone (e.g. Takahashi) who once co-authored with a Laureate is an infallible expert, whereas an actual Laureate (Altman) can be blithely dismissed…
I’m having a difficult time (which means nothing) seeing how epigenetic factors could do anything but to increase the number of feasible evolutionary pathways.
It’s “natural” for an evolutionary-computation type like me to consider modeling sundry non-genetic factors as noise in the genotype-to-phenotype map. In the sort of stuff I do, adding noise to the fitnesses of individuals is a way to smooth the fitness landscape. Does this make any sense to a biologist?
Very helpful, Allan. Thank you for taking the time to do this.
Anti-aliasing?
I’m having trouble figuring out how epigenetic changes affect populations. What is the mechanism of inheritance that survives and spreads in populations?
There are aspects of epigenetics that sound like opportunities for pharmaceutical companies.
Tom English,
I don’t see the more ho-hum kind of epigenetics as noise in the way that, say, drift might be. It’s still genes, spreading via their effects on fitness. Dawkins’s Selfish Gene was simply a stretch of DNA of indeterminate length and function, not a gene with an enzymatic product, and that’s how I’d view both transcription-factor-producing and transcription-factor-binding sequences. And, for that matter, the enzymes that change histones or methylate DNA. Those are phenotypes.
It’s really nifty to unravel how things work, and I’m sure the medical community is thrilled to gain understanding how development is modified by environmental factors.
I don’t get whatever it is that Sal is about.
Leaving aside the issue of how much gene control is done by epigenetic mechanisms as compared to transcription factors. petrushka’s point is the important one for thinking about epigenetics as a mechanism for long-term evolutionary change.
As important as epigenetic mechanisms are in development in eukaryotes, inheritance of epigenetic changes across generations seems to be very prone to the loss of the epigenetic changes. They revert after only a few generations.
Critics of evolutionary biology are always arguing that epigenetics has vast implications for explaining differences among species. No, it doesn’t! Even when epigenetic changes persist to the next generation, they are rapidly lost in the subsequent generations, unless they are stabilized by subsequent genetic changes. This has been repeatedly pointed out by evolutionary biologists, but the critics do not listen to this point.
In addition, epigenetic changes are not preferentially adaptive. If a population is stressed by, say, famine, we may be able to see effects two generations later. But they won’t preferentially be adaptive. They will perhaps be higher rates of cancer or heart disease. Not better ability to resist famine.
When people say that epigenetics is “Lamarckian” they miss this point. Lamarck’s effects of use and disuse were preferentially adaptive, and they were his mechanism for explaining adaptation. Epigenetic changes are not Lamarckian, as they are not nonrandomly adaptive.
The critics of evolutionary biology have joined in with the woo-meisters and vendors of epigenetic weight-loss ointments to peddle a fantasy version of epigenetics as a sort of magic.
Count me in as another dinosaur who doesn’t see what the fuzz is all about.
Epigenetic weight-loss ointments? Seriously?
Whoever noted the suckers born was clearly understating the truth.
ETA: Never mind…answered my own question:
http://www.epigeneticsandnutrition.com/epigenetics/resveratrol/#.VzYPOOR5BuM
Wow and just…WOW…
YECs are pleased to note that dinosaurs and humans coexist.
🙂 🙂
Seems a post of mine responding to the epigenetics weight loss bit got flagged as spam (likely due to the link I put in). Suffice to say I did not know that epigenetic weight loss ointment and other supplements were a thing. Just wow!
Just re-reading, I don’t want to give the impression that hydrophobicity effects are the only, nor even the main, means by which histone modifications may affect transcription.
Released. Thanks for the reminder to check spam.
There are also a couple of messages in spam that are 7 days old (from “chemtrails” thread. I don’t see much point of releasing them this late, but will if requested by their authors.
I am embarrassed to admit that I made up “epigenetic weight-loss ointments” off the top of my head. I knew there were “epigenetic” products of all sorts, though this seemed a bit bizarre. But just as a placeholder for epigenetic quackery of all sorts, I came up with it.
Turns out there really are such ointments marketed. Oy gevalt!
Hilarious!
So, does Rule 34 apply?
I didn’t find a full Rule 34 example, but a not safe for work search turned up “epigenetic therapy for porn addiction”.
http://sexual-addiction.weebly.com/pornography-addiction-therapy–epigenetic-inheritance-treating-pornography.html
Safe for work, mostly.
You forgot the scare quotes. But anyways, why do you think these qualify as codes?
Mung,
Oh, good grief! The Gotcha Police.
I’m just following other people’s usage, as I do when I say genetic code. I don’t rehash the same argument every time I say it.
I don’t think they exist. If it turned out they existed, one would have to see how they were implemented to judge. If one felt it mattered.
Pretty sure they were what was actually responsible for the extinction of the dinosaurs. Why be a dinosaur when you can learn to fly?
So you say code but you don’t really mean code. Is that an accurate summary? Other qualified people call it a code and that’s the only reason you call it a code. But when pressed, you don’t think it’s really a code. How do you get by?
So eukaryotes are fundamentally different from prokaryotes, or we would not be having this thread. And the mechanisms that brought this about are indistinguishable from magic.
Not magic, and not fundamentally different.
As indicated in the OP, there are at least two fundamental differences:
1.) The packing of DNA.
2.) The regulation of expression.
From the OP:
Yeah, so what, differences.
What makes those “fundamental differences” instead of just, umm, plain differences ?
I’m pale colored. And born into an American family. Does that make me fundamentally different from an African black man? People could say so … but everyone else would agree that people who define those as fundamental differences are simply bigots looking for excuses for their apartheid.
I think the answer is plain.
Mung,
Like I already said, I don’t rehash that argument every time I use a word. You have already seen my thoughts on that issue, though reading the above you haven’t understood them.
If scare quotes would have been enough to stop you going into Ass Mode, consider them present.
Mung,
Wrong.
Wrong again.
Mung,
The regulation of expression is not fundamentally different. That is rather the point of the OP.
Nor would I agree that the evolution of histones or DNA methylation are indistinguishable from magic. Unless you are saying that ALL things-that-are-different between two clades can only arise by magic.
Translation: I have nothing and know it, and I’m going to try to convince everybody else they have nothing so I won’t feel so bad about having nothing.
It’s funny because all the mechanisms of evolution are observed empirical facts.
Incomplete lineage sorting observationally happens, and we have good reason to think it did in the past too.
Horizontal gene transfer observationally happens, and we have good reason to think it did in the past too.
Convergent evolution observationally happens, and we have good reason to think it did in the past too.
Genetic Drift and Natural Selection observationally happens, and we have good reason to think they did in the past too.
Environments observationally change, and we have good reason to think they did in the past too.
Mutations observationally happen, and we have good reason to think they did in the past too.
Those mutations affect the morphology, biochemistry and physiology of the carrying organism, and we have good reason to think they would in the past too.
The phenotypical and morphological effects of those mutations affect the reproductive rate of the species, and we have good reason to think they would in the past too.
“Indistinguishable from magic”. This is why IDcreationists are often just mocked and laughed at rather than taken seriously.
I would like to point out that dinosaurs are currently over twice as diverse as mammals and live in all environments, including some where mammals do not. The only place you can find mammals but not dinosaurs is the deep ocean.
Dinosaurs don’t have much of a space program, though.
Glen Davidson
I’d say the most ‘fundamental’ (Hmmm. I think maybe my prose would be better if I used fewer scare quotes …) difference between prokaryotes and eukaryotes is that the latter are chimeric organisms, the former are not.
Let’s do a short survey. Circular chromosomes? We got ’em. Held in cytoplasm, and not a nucleus? Yep. START codon formyl methionine instead of methionine? Check. DNA not spooled on histones? By golly, that too. Not subject to DNA methylation? A cautious ‘check’. Hardly any, at least. Cardiolipin in membranes? Sure.
So the differences are actually local, depends where you look in the cell. Exceptions to any ‘fundamental’ rule can be found in every eukaryotic cell. Where?
Thanks Allan, this puts perspective on some of the occasional exchanges happening that are only peripherally related to the ID issue.
The reason the dinosaur view is suffering is the laboratory evidence. Evolutionary theories should not take precedence over lab data despite what Graur said.
Graur echoes the dinosaur view vs. the epigenetic discoveries of the NIH ENCODE consortium:
Having interacted with many of the ENCODErs personally, I find such statements disgusting. Many of the ENCODErs are medical doctors and researchers treating patients and using ENCODE data which Graur despises.
Graur should butt out, this is way outside his field of expertise. He’s just making noise.
Which ever way one wants to characterize the issue, medical researchers are confronted with the fact that broken histone systems lead to disease. This would strongly suggest histones have an important role in the functioning of life.
I could cite so many other papers like those involving the HOX cluster:
http://www.sciencedirect.com/science/article/pii/S0925477315300162
I’ve cited such papers here and elsewhere, and it falls on deaf ears. All the naysaying doesn’t bother me that much because the research money, next generation pharmaceuticals and Nobel Prizes are going to the next generation of epigenetic researchers who could care less about what is or is not politically or ideologically acceptable lab results.
Agree!
We don’t know that for sure. Transcription factors can be BLOCKED by histones and transcription factors (like the Yamanka factors) can also be regulated by microRNA’s — those “junk” non-coding RNAs pop up and are found to have function!
Below is a depiction of a microRNA network. Most networks are too complex to comprehend. Here is a depiction of one of the “simpler” microRNA networks that we have some handle on. God must really like building Rube Goldberg Machines:
So yes, dear “skeptics,” fundamentally different.
Maintenance of Epigenetic Information
Nice just-so story.
Never one to shy away from selective appeals to authority (it says so in this paper, it must be true, unless I don’t agree with it, then it’s a “just so story” or “indistinguishable from magic”) you bring us a quote erecting a synthetic distinction without merit. The last sentence you highlight is just wrong, since a fundamental dichotomy implies eukaryotes are opposites or somehow contradictory to prokaryotes.
They aren’t. They are both cellular lifeforms with a phospholipid bilayer membrane constituting a boundary delineating what is one the inside as “part of the organism” and what is outside as not, they both have DNA genomes, ribosomal translation and all but identical genetic codes, and finally they both reproduce through cell division (one cell splits and becomes two).
If they really were fundamentally different, then they would be different in their fundamental properties, such as them being cells, having DNA based genomes and reproducing by cell division. Those are the fundamental features of cellular life and they’re both shared by prokaryotes and eukaryotes. So it’s just plain wrong to say they’re fundamentally different.
But okay, you’ve brought a citation that argues the opposite. And we all know how, if it says so in a publication, it must be true and Mung believes it. Right?
Perhaps Mung just mined the wrong quote. I’m sure somewhere in his paper it uses the word magic and the phrase fundamentally different.
We are, after all, arguing ad incantatium.
First off, factors (if you mean transcription factors) are proteins not RNAs, but if you want to use an idiosyncratic notion of transcription factors, that is up to you, but I don’t find it standard in the literature.
Secondly, transcription factors can be blocked if the chromatin is inaccessible, and chromatin inaccessibility or accessibility is often dictated by the histone states.
I’ve cited this 2011 article at TSZ several times as it was the source of lecture material at the NIH — it was by one of Allis’ colleagues (Reinberg) who was the target of naysaying at Jerry Coyne’s blogs. It was featured in one of the most respected science journals.
http://www.nature.com/nature/journal/v469/n7330/full/nature09784.html
It shows how transcription factors activity can be regulated by histone states, hence it challenges the characterization that transcription factors have absolute primacy in gene regulation. I provided a graphic from that paper several times. I had to study the structure and function of the components of this complex for an exam.
I also had to give a student presentation on the laboratory experiments that examine the kinds of complexes described below. The experiment is the Chromatin Isolation by RNA Purification Sequencing ChIRP-Seq.
This describes the experimental technique:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249421/
Your characterization highlights the fight between Old School and New School viewpoints. I provide the paper in the first link on PRC2 to convey the New School viewpoint and the laboratory evidence supporting the New School view.
In the diagram below one can see the histone tail going into the bubble marked “EZH 1/2 SET” which sets the epigenetic mark on the histone tail which induces repression of the gene and blocks the activation of the transcription factor on places like the hox cluster and 832 other sites as indicated in the ChIRP-Seq paper.
It’s amusing that all the people Sal and Mung quote would reject their IDC worldview without thinking twice about it.
Regulation regulates. Who woulda thunk.
Please go look up the definition of dichotomy and also have a look at it’s synonyms.
Or i could just pull stuff out of thin air (like certain people here do) and then whine when someone cites an authority to show that I was wrong (like certain people here do).
So? Does that mean I should stop posting here at TSZ because people here reject Intelligent Design?
So much arguing about whether the word “fundamental” applies to the (largely undisputed) difference(s) here. That fight is not worth the candle, IMHO. What’s important is the specific nature of the differences, not whether they fit somebody’s notion of “essential.”
I thought y’all were scientists!
Rumraket,
Is it a correct statement to say they are fundamentally the same?
Depends on whether your head is up your fundament.
The biochemistry is the same. Mitochondrial DNA is the same code and works the same way.
Endosymbiosis is rare, but not a unique event. Multicellularity is kick started by mutations to one or two genes.
It would be quite proper to say that there are fundamental similarities.
After that it’s just a matter of semantics as to whether or not there are “fundamental dissimilarities” or some such thing. If you’re focusing on the differences you play those up, while if the continuity of life is your point you tend to emphasize the similarities.
In other words, it’s what you’d expect with non-magic evolution, increasingly great differences with greater separation of lineages, while similarities run throughout the domains.
Glen Davidson