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.
No, actually. If you bothered to think about it, you would see that mutations in things that have “an important role in the functioning of life” (e.g. catabolism, anabolism, DNA replication, transcription, translation) would more often lead to cell-lethals or embryonic-lethals, not ‘disease’. Lots of genetic diseases are caused by mutations in things that are somewhat peripheral – such as lysosome function or blood-clotting.
Well, sometimes yes, and (pay attention here) sometimes no. The problem in complex systems is distinguishing cause and effect. When scientists manipulate systems where we can distinguish cause and effect, the evidence to date is on the dinosaur’s side.
But you seem curiously unwilling to discuss the evidence, or Ptashne & Greally’s cogent argument.
argumentandum ad incantatem, indeed.
DNA_Jock,
Do you agree with this?
That’s what I did before I posted to double check that I was getting it correctly. I was. You were not.
You can do whatever you want my dear, but wrong you are.
Yes, it would be correct to say they are fundamentally the same. Since their fundamental properties are the same.
Rumraket,
Then a fish is fundamentally the same as a bird?
They both swim, just in fluids of different densities!
DNA_Jock:
Howler. Environmental factors (like say poisons or toxins), not just genetic factors can influence histone and other epigenetic systems.
In you’re eagerness to disagree, you say stupid stuff.
Fatheaded, dumb and essentialist are no way to go through life.
Said the guy who’s trying to manufacture an artificial grudge match between scientists who happen to disagree.
Everything is fundamentally the same, ’cause, you know, it’s all made of stuff.
The Greeks had a word for that.
You’re begging the question. Your stated position is that it is the shared characteristics that are fundamental. And your argument is that they are fundamental because they are shared. That’s circular.
Dinosaur or … ?
What are the fundamental properties of birds and fish?
But yeah, that could very well be true. At a fundamental level birds and fish are the same. That doesn’t mean that they are identical at every level.
I’m not arguing they are fundamental because they are shared. I’m simply stating the fundamental properties of known cellular life and noting that they are shared by both groups, which then makes it true to say they are fundamentally the same. I’m not claiming that something being shared is what makes it a fundamental property.
Rumraket,
I guess the conversation has meaning when you discuss the similarities and differences.
stcordova,
Oh dear Sal, in case you failed to notice, I was pointing out yet another of your hilarious logic fails: disruption of X causes disease, which (per Sal) “strongly suggests that X has an important role in the functioning of life”. This is the “knock-out problem”. As my psych tutor put it (in reference to Phineas-Gage-like experiments): “If you took a functioning transistor radio, and snipped a capacitor out of it, and as a result the radio now produces a high-pitched squealing sound, would you conclude that the capacitor functioned as an ‘anti-squeal capacitor’?”
Your argument is equally misplaced for environmental insults.
Locoweed inhibits alpha-mannosidase, which strongly suggests that alpha-mannosidase has an important role in what, precisely? Balance?
How about you actually address Zhang et al 2014?
Please read my first comment on this thread, comment #2.
When I originally read the Ptashne quote you cite here, I did not agree. However, my search of the literature revealed that I was wrong, and Ptashne was correct. See Zhang et al 2014
DNA_Jock,
Reading the abstract it seems that they have shown transcription without histone modification but it hardly looks like enough to conclude the argument.
I’d note in passing that I’m a dinosaur mostly because I weigh 80 tons, more or less.
Glen Davidson
colewd,
The transcription is overriding SIR-mediated silencing. According to Sal’s naive view, this chromatin is inaccessible and its transcriptional activation is impossible. The data say otherwise.
stcordova,
Of course histones have an important role in the functioning of (eukaryote) life. Have I said different? Having an important role and doing what you think they do are 2 different things.
As to the rest, I’m finding the constant pasting of picture links distracting. A picture is not always worth a thousand words.
stcordova,
I’m just going to put this here:
stcordova,
You are going from “don’t know that for sure” to “it doesn’t”. There is absolutely no caution in your posts. And yet, we do not have an example system of regulatory histone modification without TF involvement. And that’s what you need.
stcordova,
Non-coding is not synonymous with junk. How many more times?
Mung,
Because they are chimeric.
stcordova,
Only if there are ZERO RNA transcription factors would your little carp be justified. Are there zero RNA transcription factors?
And transcription factors can initiate the relaxation that allows themselves and everything else in. Rather crucial, don’t you think? A transcription factor does not have to be bound to DNA before it can have a role in transcription. What relaxes the histones in your world? The Code? TF’s buzz aimlessly against the glass like fruit-drunk wasps until The Code lets em in!
Lots of things are featured in one of the most respected science journals. They are stuffed with papers about evolution, for example. It’s pointless to puff your papers and experts up in this way.
How? How do histone states exert a causal effect on transcription factors? I know how TFs exert a causal effect on histone states, but not the other way round. What strange magic unwinds the histones so that TFs can get in? How does it encourage them to be in place, waiting?
Mung,
So you side with the Sals of this world, but can’t really say why?
colewd,
What argument – that we should accept the primacy of histones pending actual evidence thereof?
Allan Miller,
Argument according to Jock.
colewd,
If transcription without histone modification is held to be not possible, and it is observed, isn’t that fairly conclusive?
Allan Miller,
If that is Sal’s true argument….you bet.
Isn’t it obvious?
They say there’s a first time for everything, but don’t tell Sal.
But no.
Rumraket,
Lessee. Fishes and birds are both vertebrates. So, roughly 3 billion years of common lineage, then less then 400 million years divergence. Now look at morphology. Compared to the non-vertebrates, differences between types of vertebrates are minor.
colewd,
Sorry, you’re confusing me. You talk vaguely of ‘Jock’s argument’, and now ‘Sal’s true argument’ … which argument do you mean when you say that the observation of transcription without histone modification is not conclusive of ‘the argument’. Could you express this argument in a couple of sentences?
Mung,
So a self-described ‘dinosaur’ (ooh look – scare-quotes) could actually have his head in the sand, in rejecting an argument you don’t agree with anyway.
Of interest
Post-transcriptional regulation is part of the cascade. Once histones have relaxed/been relaxed, transcription factors have initiated transcription and an mRNA been produced, there is a substantial opportunity for control of translation and feedback to transcription, and these authors regard this as the most significant control, even further removed from the putative histone code.
This, indeed, is a very plausible reason why pervasive transcription has been detected by the likes of ENCODE – because the DNA level is not in fact where the principal control steps are located at all. You have to transcribe to determine whether further processing is to be initiated. For analogy fans, you have to open the book to see if it’s full of shite.
Also worth noting that RNA readily binds to RNA, and thus can have a posttranslational role. A pedant may wish to restrict the repertoire of functional molecules to protein.
Allan Miller,
Since Jock claims here that Sal’s position is, transcription is impossible when chromatin is folded and Jock with the 2014 paper showed experimental evidence that it is possible then Jock wins the gambit assuming he has not created a “straw man” to Sals argument. When you say something is impossible you better have your ducks in a row.
colewd,
Great, thanks for clarifying.
I didn’t say “DOES”, I said “CAN” as in “histones can block transcription”. You like DNA_jock knocked down an argument I didn’t make. Tiresome.
Additionally, if a transcription factor binds, the chromatin is accessible by definition as far as that factor is concerned. DUH!
As far as this whole thing about Transcription Factors being primary, the problem is that in network topologies like the internet and gene regulatory networks, there is decentralization rather than centralization of control.
It is as meaningless to argue what is the central component in a gene regulatory network as it is to argue what is the central component to the internet and the world wide web. Allan’s view is a dinosaur view, and dinosaurs by the way, went extinct.
A diagram that shown those junk RNAs that evolutionary biologists seem to hate having a influential (not necessarily absolutely central) role in controlling transcription factors! So what is the central issue or molecule? Maybe there is none, that is the nature of networks that are designed to be robust to damage and injury or other functional compromises. There is no one thing absolutely central or fundamental, and that is by design.
https://openi.nlm.nih.gov/detailedresult.php?img=PMC2764428_gkp638f4&req=4
stcordova,
You agree that certain TFs can overcome heterchromatin silencing, and others cannot, depending on the TF. So you admit that TFs are driving the bus. Awesome news!
Now, if you could walk us through, in your own words, how histone methylation & acetylation patterns are replicated, and what the evidence is to support your proposed mechanism, that would be just peachy.
Or you could address PtaShne and Greally, or address Zhang et al 2014. Or do you have nothing except hilariously selective appeals to authority?
LOL.
ETA: Make that “hilariously selective appeals to authority and hopelessly lame analogies”
TGTKOG
Finally, the reveal!
Do you have any evidence for that assertion, or will you just be leaving it hanging out there on it’s own, all lonely like?
stcordova,
Just to point that, if ‘you’ meant me, I didn’t write that, DNA_Jock did. It was blockquoted to me by colewd. So ‘You like DNA_Jock’ means ‘DNA_Jock like DNA_Jock’. We’re easily confused.
Indeed. And what lets it in?
Yeah, like SRY in therians or MAT in yeast. Yeah.
And exactly how is that decentralized control passed from generation to generation, and how do modifications spread in a population?
stcordova,
It is more a question of information flow than centrality. There is ‘upstream’ and ‘downstream’ in chains of causality (not to be confused with upstream and downstream on DNA strands).
Wow. A devastating blow in an OP entitled … 🙂
Therefore old ideas are always wrong? So much for Creationism then!
I don’t know where you lot get this idea from. RNAs are either functional or nonfunctional. I have no greater affection for one over the other.
You see the same crap all over – people demand better evidence for some flight of fancy, they ‘hate’ the shining new paradigm. And evolutionary biologists hate them most of all? But why? There’s nothing in epigenetics that poses any threat to evolution. Though there is a huge amount of hype.
Contrariwise, as an RNA worlder, I am delighted to find RNAs very near the head of the causal chain. You picked me up on it when I used the more general term ‘factors’ to include protein and RNA.
I agree, and I think you misunderstand if you think that is contrary to what people are saying in general.
It’s not all that robust, really. Hence spending billions of pounds trying to fight its failures.
You’re sure about that then? What does design have to do with it? If there were a central component, would that be by design too? Well yes of course it would. Design is that which explains anything and everything one happens to put forward as a phenomenon. In which case, why (as I have asked before) are Creationists so keen to assert that the design consists of a histone code, and not TF-initiated cascades with histone remodelling downstream?
The bus can’t go anywhere if the road is blocked by histones. From the Journal Nature, a diagram showing how histone acetylation blocks chromatin accessibility and thus blocks transcription factors:
From the caption:
http://www.nature.com/nrm/journal/v16/n4/fig_tab/nrm3931_F4.html
Gee, that reads like the histones are almost like gate keepers to that transcription factor bus you boast about. The nature article accords well with the description I provided — like maybe because I got my description from mainstream literature rather than naysayers at TSZ.
And worse, the description agrees with the themes in that hated New Yorker article.
heh