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?

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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