Tuesday, July 29, 2008

Epigenetics Revisited

 
I'm still struggling with the concept of epigenetics [see Epigenetics]. Most of the modern definitions are so broad that they become meaningless. It's impossible to distinguish between epigenetics and plain old regulation of gene expression.

One of my colleagues, Craig Smibert, was so annoyed by my questions about epigenetics that he pointed me to a series of articles in Nature in the hopes it would shut me up. The relevant article is Perception of Epigenetics by Adrian Bird (Bird 2007).

It's not going to help. After describing several examples like methylation and histone modifications, Bird then points out that these modifications are not necessarily stable ...
So how accurately transmitted should an epigenetic mark be? Variation due to faulty copying is compounded by current evidence that all histone modifications, as well as DNA methylation itself, can be abruptly removed during development, thereby preventing the persistence of these modifications in a heritable epigenetic sense.
In other words, an epigenetic phenomenon doesn't really need to be heritable in order to qualify as epigenetic.

Furthermore, an epigenetic phenomenon doesn't even have to be passed on to progeny to qualify.
The restrictiveness of the heritable view of epigenetics is perhaps best illustrated by considering the brain. A growing idea is that functional states of neurons, which can be stable for many years, involve epigenetic phenomena, but these states will not be transmitted to daughter cells because almost all neurons never divide.
That's not very helpful. It's beginning to look like any activation or repression of eukaryotic genes will count as epigenetics. (According to some, it doesn't have to be eukaryotes. There is epigenetic regulation in bacteria as well, Casadesús and Low (2006).)

Here's the definition ...
Given that there are several existing definitions of epigenetics, it might be felt that another is the last thing we need. Conversely, there might be a place for a view of epigenetics that keeps the sense of the prevailing usages but avoids the constraints imposed by stringently requiring heritability. The following could be a unifying definition of epigenetic events: the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states.
Does this include simple activation and repression of genes during development in the manner of control of lac operon expression? You betcha.

Bird may be thinking mostly of histone modifications and DNA methylation but he's well aware of the fact that these are often consequences, not causes, of activation and repression. He says,
For example, transcriptional activation through sequence-specific DNA-binding proteins brings in histone acetyltransferases, which then epigenetically adapt the promoter region for transcription (for histone acetyl groups, although ephemeral, would now be epigenetic).
So we're right back where we started, Craig will not be happy. Just about anything that modifies or regulates gene expression in eukaryotes (multicellular?) counts as epigenetics.

One could ask, what's the point? Why create a special word to describe regulation of gene expression in eukaryotes (and prokarotes) using mechanisms that we've known about for thirty years?


Bird, A. (2007) Perceptions of epigenetics. Nature 447:396-398. [doi:10.1038/nature05913]

Casadesús, J. and Low, D. (2006) Epigenetic Gene Regulation in the Bacterial World. Microbiology and Molecular Biology Reviews 70:830-856. [doi:10.1128/MMBR.00016-06

20 comments:

  1. Science have a big online feature that probably won't help you!:

    http://www.sciencemag.org/feature/plus/sfg/resources/res_epigenetics.dtl

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  2. "regulation" is only satisfactory for the philosophically lightweight, like Larry, who think everything's genetic and basically represented in the operon lac.

    Epigenesis is actually a much older developmental abstraction that has absolutely nothing to do with "gene regulation"

    Yes, Larry, this is on one of those cases where "being philosophical" is actually thinking things through, instead of just believing in a cartoon.

    I can't blame you too much, Larry. You're just following the larger, gene-happy crowd. Even "epigeneticists" sometimes fail to realize that it's not all about "gene regulation". Maybe that's why you don't think it's convincing...everyone panders to the gene to get money.

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  3. The trouble with calling it all "transcriptional regulation" is that it fails to distinguish between two levels of regulation.

    The first is completely reversible, and is examplified by stuff like the lac operon. Supply a given metabolite, and a set of enzymes are induced. Withdraw that metabolite, and the enzymes are switched off again.

    The second is irreversible on the time scale of the individual cell, and moreover is propagated through cell divisions to the daughter cells. Examples include X inactivation, gene imprinting, PSI+ conversion in yeast, and so on. This second is the domain of epigenetics. If you want a formal definition, I would say that an epigenetic change is one which
    a) Does not alter the base DNA sequence
    b) Persists in the absence of the stimulus that originally caused the change
    c) Persists through cell division

    There is a profound difference between these two levels of regulation, and it's silly to obscure it.


    Of course, all the stuff about "new Lamarckism" is nonsense. For epigenetic change to lead to Lamarckian inheritance, it would firstly need to persist not just through cell division, but through multiple generational passage through the germ line - a much more stringent requirement. Secondly, it would need to be a directed response to external stimuli, breaking the separation of somatic and germ cell lineages. Epigenetics does not do this, though there are certainly a few edge cases where (for example) uterine conditions can lead to multi-generational change in gene expression.

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  4. We all know that the activity of the operon lac has components that are in no way "encoded" in the operon itself, such as the availability of the lac represor, and exposure to lactose itself.
    As in the operation of any machine (such as this computer), structural organization, spatial arrangements, etc is crucial. To say that everything is "gene regulation" is as goofy as saying my computer is all "silicon chip regulation". It sound like truth at some cheesy level but scientifically it is useless.

    To hold on to their reductionism, those who believe it is all ultimately about sequence composition are forced to use some ugly metaphor, such as "program" or "code", a blueprint of the organism, to somehow blame primary sequence for everything.

    Some really seem to "go" for it, but for the rigorous biophilosopher this is just material for giggles.

    Peter says

    "It would firstly need to persist not just through cell division, but through multiple generational passage through the germ line"

    How do you think imprinted genes originate?
    Are you saying there is no possible role of environmental induction in the origin of any imprinted gene?

    The way you think "by necessity" imprinted genes would only originate exclusively via sequence changes.

    I don't think that's true.

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  5. I'm with Peter. Also, environmental factors have nothing whatever to do with imprinting.

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  6. "environmental factors have nothing whatever to do with imprinting"

    Hahaha

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  7. Peter says,

    There is a profound difference between these two levels of regulation, and it's silly to obscure it.

    I disagree. They are just variations on a theme. Proteins bind to DNA and those proteins control the expression of the gene. The proteins can be repressors, activators, modulators, or histones, and the proteins, in turn, can be covalently modified.

    Direct modification of DNA is a bit different but it's been known for 30 years without any scientist feeling the need to invoke a new word to describe this kind of modification.

    Same thing applies to gene rearrangements; also known for 30 years without provoking a revolution in our understanding of the regulation of gene expression.

    Besides, your restricted definition of epigenetics doesn't seem to be shared by most advocates who are happy to apply the term to very simple, and reversible, forms of gene regulation.

    I think this is just an attempt by the evo-devo crowd to make their study of (mostly) animal development seem more important than it really is. They're not happy with Monod's statement that what's true for E. coli is also true for elephants.

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  8. While what's true for E. coli may also be true for elephants, the reverse is not. There is no E. coli version of X-inactivation, either mechanistically or phenomenologically. I don't know about "advocates", but Peter's definition is what we teach our graduate students.

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  9. "I think this is just an attempt by the evo-devo crowd to make their study of (mostly) animal development seem more important than it really is. They're not happy with Monod's statement that what's true for E. coli is also true for elephants"

    That's sweet, but most evo-devos are as reductionist as you are, Larry, specially those who love cis-regulation paradigms.

    Only a few evo-devos are favoring a central role for epigenetics in evolutionary theory.

    You should know better; research in epigenetics is not published in evo-devo magazines. Epigenetics actually is coming mostly from genetics people and unfolding ever since the discovery of non-mendelian genetics. It has explained human genetic diseases that would not be explained only by observing the primary sequence. There is nothing more succesful than success, and this is a research program that works.

    I will agree that it is silly when people toot the revolution horns. Do you know for how long have people been proclaiming the death of ultradarwinism? I'll just say we can expect dawkins-crap for quite some time more, for reasons more akin to the endurance of ideologies. It does not depend on the science.

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  10. By the way, too, a GREAT deal of the more fascinating stuff in epigenetics has been shown using plants as model systems.

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  11. evo-devo journals only publish a small fraction of the studies on epigenetics

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  12. anonymous says,

    I don't know about "advocates", but Peter's definition is what we teach our graduate students.

    I'm truly sorry to hear that. I always try to teach students to look at the similarities between all organisms. This reflects their descent from a common ancestor.

    My goal has always been to prevent students from thinking that eukaryotes are very different from bacteria. That kind of attitude encourages them to ignore all the work that was done with bacteria and bacteriophage and that's a very bad thing, in my opinion.

    What school do you teach at?

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  13. That'll be the same school where Larry teaches epigenetics and postmodernism hahahaa

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  14. It's a major American medical school / university. We need to explain the inheritance of things like Prader-Willi / Angelman syndrome to the med / grad students. There doesn't appear to be an appropriate bacterial or phage paradigm. As an exception to the Mendelian inheritance rule, and as a significant factor in cellular differentiation in multicellular organisms, epigenetics is a well-established phenomenon with a precise mechanistic explanation and clear clinical implications. We can't / won't ignore, minimize or obfuscate epigenetics. Maybe understanding the differences between eukaryotes and bacteria will help add to an appreciation of the commonalities.

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  15. Anonymous says,

    As an exception to the Mendelian inheritance rule, and as a significant factor in cellular differentiation in multicellular organisms, epigenetics is a well-established phenomenon with a precise mechanistic explanation and clear clinical implications.

    Could you enlighten me by posting the "precise mechanistic explanation" of epigenetics?

    While you're at it, could you explain why the restriction modification system in bacteria doesn't qualify as epigenetics.

    Do you know anything about sporulation in Bacillus subtilis? It's a well-understood example of multicellular differentiation in prokaryotes. Is it epigenetics?

    Here's the abstract of a paper by Grandjean et al. (1998). It documents chomatin inactivation in B. subtilis—an effect that's very similar to X-inactivation in mammals.

    Epigenetic mechanisms are not exclusively reserved to eukaryotic organisms. They are also observed in prokaryotes. As described first by Hotchkiss and Gabor, protoplast fusion between strains of Bacillus subtilis produces heterodiploid cells. Heterodiploidy is associated with the inactivation of one of the chromosomes. To study the physical structure of the fusion product and the molecular mechanisms of inactivation, we constructed heterodiploid clones containing two chromosomes labeled by a NotI restriction fragment length polymorphism. In the progeny, we identified haploid recombinant clones that contain a chromosome carrying large regions of inactivated DNA. Studies of both recombinants of the latter kind and heterodiploid cells indicated that chromosomal inactivation was not determined by alteration of the inactivated nucleotide sequence, but was probably due to a modification in the structure of the bacterial chromatin.

    The problem seems to be that many scientists have completely ignored all the work on gene expression in bacteria.

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  16. I don't get Larry's "bacterial" point.
    Epigenetics is also in the bacterial world, of course. They are organisms, not strands of DNA. Plus I predict you will find methylation-related responses to the environment in bacteria. Which will possibly be inheritable.

    Epigenesis refutes any situation in which the DNA is made to look like a "program" or homuncule determining everything that goes on in the organism. Any organism: single-cell, plant, animal... in all, DNA reductionism is false

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  17. Could you enlighten me by posting the "precise mechanistic explanation" of epigenetics?

    Epigenetics is the modulation of gene expression in large chromosomal domains mediated by cooperative, persistently maintained, covalent modifications of chromatin.

    This is how we teach it. You might hear differently elsewhere, or even everywhere. What do your colleagues use as a definition for teaching grad students at your institution?

    While you're at it, could you explain why the restriction modification system in bacteria doesn't qualify as epigenetics.

    i) The methylation associated with RM systems is not cooperative: methylation of each recognition site is independent of methylation at other sites.

    ii) RM systems don't broadly modulate gene expression.

    --

    Note to sanders: I disagree with your statement that "Epigenesis refutes any situation in which the DNA is made to look like a "program" or homuncule determining everything that goes on in the organism." Epigenesis is simply one way (of many) in which the cellular "program", as determined by the primary sequence of the DNA, can be dynamically modulated.

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  18. There are many "modern" definitions of epigenetics. Larry is right to point out that it is not always used in relation to inheritance, but basically to anything that goes beyond the primary sequence of DNA. Methylation is talked about as epigenetic simply because it is not a change in the primary sequence, regardless of whether it is inherited or not.

    I don't like your definition, specially the large chromosomal domains thing... merely descriptive, unnecessarily restrictive.

    Notice I use the word epigenesis, not epigenetics, to make it clear that I use an older conception of the word: the refutation of preformism, the idea that the phenotype is merely the "expression" of a "plan" or "program".

    Simple question:
    How can you say the primary sequence contains the "cell program", when different cell types of your body have exactly the same DNA sequence?

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  19. The word epigenetics has been used to bundle together a diversity of mechanisms, mostly regarding how the environment of a gene can affect gene expression, even between generations. I consider it is a new brand of genetics, with a a developmental edge, that has become aware of the role of the environment in heredity.

    It is true that this is no clear-cut definition of what epigenetics is. Yet this does not mean there is nothing to it. You'd be surprised at the amount of fools who think just EVERYTHING is genetics; and yet there IS something after all to that "genetics" thing, isn't there.

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  20. Another thing that Larry should know perfectly well is that it is as false to say what's true for E.choli is true for elephants as it is to say vice-versa. Any lineage will accumulate "unique" traits (autapomorhies). Further, bacteria can retain many primitive traits that have been completely lost in the elephant.

    "Bacteria" is where we find some of the oldest divergences, so comparison to bacteria is fundamental to establish things that are common to all life (or at least ancestral). That does not mean that what is true for the bacterium is true for the elephant. I can dish out some examples of where it is not.

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