What Is Epigenetics?

 
Berger et al. (2009) attempt to define epigenetics.

"An epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence."

Sounds good to me. Just about anything wold be better than the kitchem sink definition proposed by Eva Jablonka [Epigenetics at SEED].

The main examples are "DNA methylation, histone modifications, histone variants, and nucleosome positioning." These are chromosomal alterations that are passed on to daughter cells following cell division by mitosis or meiosis.

Although the Berger et al. don't mention it, these epigenetic signals are all reversible. I still don't find the term useful. It's far more accurate to refer to each of the individual examples by name and the field is "regulation of gene expression."

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Berger, S.L., Kouzarides, T., Shiekhattar, R., and Shilatifard, A. (2009) An operational definition of epigenetics. Genes & Dev. 23:781-783. [DOI: 10.1101/gad.1787609]

[Hat Tip: Hopeful Monster]

Regulatin' Genes

 
Some of us old fuddy-duddies have been learning about the regulation of transcription for over forty years. When you've been teaching about regulatory proteins, like HOX proteins, for twenty-five years, the novelty sort of wears off.

It's fun to see the enthusiasm of students who have just recently been "turned on" by gene regulation, especially when one of them is also a Toronto Blue Jays fan! Strange that the university looks a lot more like Stanford than the University of Toronto [HumBio instructor, students rap about science on YouTube].

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Epigenetics, Again

 
The National Institutes of Health (NIH) have launched a $190 million research effort to learn about epigenetics. According to Nature News ...
It’s not that epigenetics is totally useless. I just don’t see why it’s worth 190 million dollars.

Kevin Struhl
Harvard Medical School

Epigenetics, described as "inheritance, but not as we know it"1, is now a blisteringly hot field. It is concerned with changes in gene expression that are typically inherited, but not caused by changes in gene sequence. In theory, epigenetic studies can help explain how the millions of cells in the human body can carry identical DNA but form completely different cell types, and perhaps why certain cells are susceptible to disease.

The NIH's epigenomics initiative is a plan for such studies on a grand scale including, for example, surveys in different human cell types of all the chemical tags, or epigenetic marks, that might control genes.

It seems strange to be spending so much research money on something that scientists can't even define properly [Epigenetics in New Scientist, Epigenetics Revisited, Epigenetics]. Perhaps some of this money will go toward coming up with a reasonable definition of what they're studying.

As far as I know we already have a good model for how totipotent cells can differentiate into many different cell types. We also understand how they can revert to pleuripotent cells. We even know that differentiated cells can be transformed back into stem cells by adding certain transcription factors.

Now we add in the fact that some DNA binding proteins can covalently modify DNA and this affects gene expression. What's the big deal?

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An Example of Faulty Logic from Cold Spring Harbor

A press release from Cold Spring Harbor Laboratory promotes the work of Michael Zhang and Adrian Krainer who work with splicing factors. In a typical attempt to hype the significance of the work, the press release claims that each human gene has many different variants produced by alternative splicing [CSHL team traces extensive networks regulating alternative RNA splicing].

That may or may not be correct—I happen to think it's mostly an artifact of EST cloning—but that's not the point I want to make here. The main point is the rationalization explained thus,

Biologists involved in the Human Genome Project were frankly astonished to discover that everything that makes us human is the product of a set of only 23,000 or so genes.¹ That number in itself, though several times smaller than prior estimates, is not shocking; it is the relative size of other genomes that surprised scientists.

The common fruit fly that hovers over your ripening bananas, for instance, possesses some 14,000 genes. It's perfectly obvious that human beings are vastly more complex, biologically, than a fly. Molecular biologists have demonstrated in recent years that it is not the number of genes that is the key to complexity but rather the number and diversity of gene products that a given set of genes can instruct cells to manufacture.

Rather than a single gene ordering the production of a single kind of protein, as scientists used to assume, it turns out that individual genes can in some cases give rise to dozens or even thousands of different proteins, thanks to a phenomenon called alternative splicing.

This is one version of what I call The Deflated Ego Problem. The "problem" is that some people are really, really, upset about the fact that humans may only have a few thousand genes more than a fruit fly.

So they look for some way to reflate their egos and one of the most common arguments is the one shown above. (It's excuse #1 on the list.) It goes like this.... Humans are so much more complex that fruit flies even though they have only a few thousand more genes because each human gene does double, or triple duty. Each human gene makes several different proteins by alternative splicing of the primary RNA transcript.

Viola! Problem solved.

Except for one little nasty fact. Drosophila genes also show abundant levels of alternative splicing. In fact they produce just as many variants per gene as humans, if you believe the EST data (which I don't).

Oops. There goes that solution. Humans don't have that many more proteins than fruit flies after all.

This is such an obviously bogus argument that I'm surprised it still appears in the scientific literature. Doesn't anyone realize that in order for it to salvage deflated egos there has to be no—or much less— alternative splicing in fruit flies?

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Some people were surprised and embarrassed by the "low" number of genes in the human genome but others were pretty happy that their estimates were close to the mark [Facts and Myths Concerning the Historical Estimates of the Number of Genes in the Human Genome].

Epigenetics in 1952-53

 
This week's Citation Classics are, indeed, classics [This Week's Citation Classics: Host Induced Variation]. They were the first papers to describe a new form of non-Mendelian inheritance that eventually became well-understood at the molecular level. Today, scientists working on animal development think they have independently discovered this concept. They call it epigenetics.

As John Dennehy says,

Today epigenetics is all the rage, but it has its roots in a pair of papers appeared nearly simultaneously in 1952-1953.

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