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.