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Derek Lowe The 2002 Model

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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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April 25, 2013

What The Heck Does "Epigenetic" Mean, Anyway?

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Posted by Derek

A lot of people (and I'm one of them) have been throwing the word "epigenetic" around a lot. But what does it actually mean - or what is it supposed to mean? That's the subject of a despairing piece from Mark Ptashne of Sloan-Kettering in a recent PNAS. He noted this article in the journal, one of their "core concepts" series, and probably sat down that evening to write his rebuttal.

When we talk about the readout of genes - transcription - we are, he emphasizes, talking about processes that we have learned many details about. The RNA Polymerase II complex is very well conserved among living organisms, as well it should be, and its motions along strands of DNA have been shown to be very strongly affected by the presence and absence of protein transcription factors that bind to particular DNA regions. "All this is basic molecular biology, people", he does not quite say, although you can pick up the thought waves pretty clearly.

So far, so good. But here's where, conceptually, things start going into the ditch:

Patterns of gene expression underlying development can be very complex indeed. But the underlying mechanism by which, for example, a transcription activator activates transcription of a gene is well understood: only simple binding interactions are required. These binding interactions position the regulator near the gene to be regulated, and in a second binding reaction, the relevant enzymes, etc., are brought to the gene. The process is called recruitment. Two aspects are especially important in the current context: specificity and memory.

Specificity, naturally, is determined by the location of regulatory sequences within the genome. If you shuffle those around deliberately, you can make a variety of regulators work on a variety of genes in a mix-and-match fashion (and indeed, doing this is the daily bread of molecular biologists around the globe). As for memory, the point is that you have to keep recruiting the relevant enzymes if you want to keep transcribing; these aren't switchs that flips on or off forever. And now we get to the bacon-burning part:

Curiously, the picture I have just sketched is absent from the Core Concepts article. Rather, it is said, chemical modifications to DNA (e.g., methylation) and to histones— the components of nucleosomes around which DNA is wrapped in higher organisms—drive gene regulation. This obviously cannot be true because the enzymes that impose such modifications lack the essential specificity: All nucleosomes, for example, “look alike,” and so these enzymes would have no way, on their own, of specifying which genes to regulate under any given set of conditions. . .

. . .Histone modifications are called “epigenetic” in the Core Concepts article, a word that for years has implied memory . . . This is odd: It is true that some of these modifications are involved in the process of transcription per se—facilitating removal and replacement of nucleosomes as the gene is transcribed, for example. And some are needed for certain forms of repression. But all attempts to show that such modifications are “copied along with the DNA,” as the article states, have, to my knowledge, failed. Just as transcription per se is not “remembered” without continual recruitment, so nucleosome modifications decay as enzymes remove them (the way phosphatases remove phosphates put in place on proteins by kinases), or as nucleosomes, which turn over rapidly compared with the duration of a cell cycle, are replaced. For example, it is simply not true that once put in place such modifications can, as stated in the Core Concepts article, “lock down forever” expression of a gene.

Now it does happen, Ptashne points out, that some developmental genes, once activated by a transcription factor, do seem to stay on for longer periods of time. But this takes place via feedback loops - the original gene, once activated, produces the transcription factor that causes another gene to be read off, and one of its products is actually the original transcription factor for the first gene, which then causes the second to be read off again, and so on, pinging back and forth. But "epigenetic" has been used in the past to imply memory, and modifying histones is not a process with enough memory in it, he says, to warrant the term. They are ". . .parts of a response, not a cause, and there is no convincing evidence they are self-perpetuating".

What we have here, as Strother Martin told us many years ago, is a failure to communicate. The biologists who have been using the word "epigenetic" in its original sense (which Ptashne and others would tell you is not only the original sense, but the accurate and true one), have seen its meaning abruptly hijacked. (The Wikipedia entry on epigenetics is actually quite good on this point, or at least it was this morning). A large crowd that previously paid little attention to these matters now uses "epigenetic" to mean "something that affects transcription by messing with histone proteins". And as if that weren't bad enough, articles like the one that set off this response have completed the circle of confusion by claiming that these changes are somehow equivalent to genetics itself, a parallel universe of permanent changes separate from the DNA sequence.

I sympathize with him. But I think that this battle is better fought on the second point than the first, because the first one may already be lost. There may already be too many people who think of "epigenetic" as meaning something to do with changes in expression via histones, nucleosomes, and general DNA unwinding/presentation factors. There really does need to be a word to describe that suite of effects, and this (for better or worse) now seems as if it might be it. But the second part, the assumption that these are necessarily permanent, instead of mostly being another layer of temporary transcriptional control, that does need to be straightened out, and I think that it might still be possible.

Comments (17) + TrackBacks (0) | Category: Biological News


1. Vader on April 25, 2013 9:04 AM writes...

"The Wikipedia entry on epigenetics is actually quite good on this point, or at least it was this morning"

I sense another round of citogenesis coming on.

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2. biotech scientist on April 25, 2013 9:45 AM writes...

I think that Ptashne is over-simplifying here. To just consider the recruitment of transcription factors-says to me, the whole chromosome is available for transcription at all times? What transcription factors can bind to heterochromatin? Our cells would be the size of baseballs if everything was unwound available.

Call me crazy, but there is more going on here than simple binding.

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3. biotech scientist on April 25, 2013 10:08 AM writes...

There are transcription factors that bind heterochromatin...I feel dumb, thought that was impossible. I should have said constitutive RNA polymerase activty in heterochromatin.

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4. medchemgrad on April 25, 2013 10:15 AM writes...

Isn't there evidence that histone modifications are heritable, that some survive reprogramming, and that an environmental stimulus can alter the histone modifications and change phenotype across generations?

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5. HI on April 25, 2013 11:04 AM writes...

My research is in chromatin field. A lot of people, including my boss, use words like "epigenetics" and "epigenome" to describe what we study, but I am uncomfortable about it because of all the things that Ptashne says.

On the other hand, as biotech scientist in comment #2 points out, Ptashne tends to simplify everything to a matter of binding and recruitment. There is no question that that is what transcription factors do and it is understandable that he wants to emphasize it considering his research career. But things get a little more complicated when there is chromatin.

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6. Big Freddie on April 25, 2013 11:18 AM writes...

Hi, I think the concept of the heritability of epigenetic modifications stuff got going with the overkalix studies on the effect of feeding levels (overfeeding, starvation etc) on health effects in later generations. These results are virtually absent from the reviewed literature however so...we don't know what to make of them. It is clear that oogenesis and spermatogenesis strips out most epigenetic signals prior to laying down maternal and paternal imprints. The imprinting mechanism does show some environmental susceptibility at least in rodent models...but this is not inheritance in a classic is just cell biology and somatic/environmental effect on gametogenesis..i.e the grand paternal or grand maternal imprint has nothing to do with the maternal or paternal imprint. With the maternal side there is a complication...a pregnant woman undergoing starvation is starving her fetus...and her fetus' germline as it is undergoing meiosis one and is metabolically active. Hence...the appearance of both a maternal, and grandmaternal effect on a population could just be a "russian doll" problem...a pregnant woman in effect is three generations in one...herself representing her generation (..duh..Dr. Obvious here) her fetus experiencing a starvation stress and the fetal germline cells also experiencing the stress. The generational compression is confusing and may be a source of some of this. I know imprinting is somewhat mosaic in terms of demethylation/remethylation and meiotic stage so there is probably some gene by gene variation in terms when this is occurring, which might matter as well. Anyway, surveying the lit a bit it is confusing, and I think often the authors are forgetting what a pregnant woman is...three generations in one :-)

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7. franko on April 25, 2013 11:35 AM writes...

What do you mean by "bacon-burning"? The argument is getting over-heated?

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8. RKN on April 25, 2013 12:42 PM writes...

So if covalent labeling of DNA (e.g., methylation) is transient and not permanent, then are all the papers that claim methylation patterns can be used, for instance, to prognose disease outcome, fundamentally wrong?

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9. Christophe Verlinde on April 25, 2013 1:13 PM writes...

Lots of people have hijacked the term epigenetics because it creates a sense of innovation, potentially useful when they are trying to get their grants score higher than the competition. This buzzword also may may also work to win the hearts of editors and manuscript referees.

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10. alig on April 25, 2013 1:55 PM writes...

It is all semantics. Hell, our former President Clinton famously argued about the definition of the word "is". Words can mean different things to different people and that doesn't make them wrong.

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11. Hap on April 25, 2013 2:26 PM writes...

Words mean what people agree they do, but there are reasons to make their meaning (particulalrly in a limited and technical context) clear. If one group is saying something with a word and the audience takes it to mean something different, there could be problems. When one group uses a word to smuggle in meanings by a term so that they can gain acceptance (or at least avoid censure) for a meaning unlikely to be accepted openly, groups may unwittingly cede control over their language and ideas to them. Finally, terms are useful as brief encapsulations of phenomena; if they are used by others for less specific meanings (because they sound cool or educated, or because they're not sure how to name what they mean precisely), they cease to be useful and unambiguous and no longer can be used well for their original meaning. The last renders the language less useful because there will be a word that doesn't mean much and a space (because there's a set of phenomena that can no longer be explained concisely) in place of a word that described something accurately and well, and thus people can no longer say clearly what they mean for some interval of time.

Semantics is important sometimes.

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12. really? on April 25, 2013 5:15 PM writes...

Perhaps the safe ground is to refer to "chromatin regulation" for the effect of many histone modifications and steer clear of the inheritance originally included in "epigenetic"?

Was at a recent meeting w Patashne and the newer kids on the chromatin block. As a chemist, it was a somewhat entertaining dust up, but maybe not so illuminating. While it is helpful for him to remind the naive (like me) of the backstory, he was also ignoring a lot of pretty solid new data - which he apparently had not read.

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13. Insilicoconsulting on April 25, 2013 10:06 PM writes...

A biologist from a very prominent epigenetics company got very uncomfortable when questioned as to whether their epigenetics drug effects could affect the next generation.

Then we realized that the person had completely forgotten about the original meaning of the work epigenetic and thus the humming and hawing...

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14. meshugena313 on April 26, 2013 8:17 AM writes...

My lab studies chromatin, so I'm smack in the middle of this, and in fact conceptually this has been a long running debate that most investigators in the field are aware of, and many agree with Ptashne. There was a classic Keystone meeting two years ago entitled "Histone Code: Fact or Fiction?".

Two issues that I have - first, most of this debate glosses over mitotic vs. meiotic inheritance. The meiotic inheritance of epigenetic information (regardless of how this mechanistically acts) has limited, but clear, bona fide observations in certain fields. Most people when using the word "epigenetic" are actually referring to mitotic inheritance in which memory of prior transcriptional states clearly exists. Is this due to continued dynamic signals or due to post-translational modification of histone mods, deposition of histone variants, or DNA modifications, that are copied during S-phase? Probably both, according to current evidence. The recent flurry of papers showing roles for histone variant H3.3 in marking active genes, and the zillions of ChIP-Seq papers showing H3K4me3 as the best mark of a promoter (much better than any DNA sequence), and the old ('70s) evidence of conservative histone inheritance, shows that chromatin is itself an information store.

Ptashne is also looking at this primarily from the Jacob and Monod approach, in which E. coli and elephants are the same. That's not even remotely true anymore, not even sure that J&M had much support for that in the beginning.

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15. darwinsdog on April 26, 2013 1:48 PM writes...

I just assume when we preface anything with 'epi' (or 'omic' as suffix) that it is a placeholder for when we figure it out. Not to be confused with those equally useless modifiers (ex. nano, high-throughput/content/performance) that label well understood things but which make something sound more 'sparkly' in some non-quantitative fashion.

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16. Jraab on April 27, 2013 7:59 PM writes...

I think Ptashne misses a good recent reference on epigenetic memory experiments. .
Hawthorne showed pretty convincingly that silencing can persist, in the absence of the initiating signal, until a new activating signal occurs.

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17. Anonymous on May 2, 2013 3:01 PM writes...

darwinsdog: You clearly don't subscribe to the belief that nano-epigenomics in which one analyzes, via high throughput, content rich determinations of the state of DNA methylation are of any value in accelerating translational research from the bench to the bedside. Why not? It's got all the buzz words in it.

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