The Epigenetics Revolution

Certain regions of our chromosomes have an extreme form of that sort of structure almost all the time. These tend to be regions that don’t really code for any genes. Instead, they are structural regions such as the very ends of chromosomes, or areas that are important for separating chromosomes after DNA has been duplicated for cell division.

The regions of DNA that are really heavily methylated also have this hyper-condensed structure and the methylation is very important in establishing this configuration. It’s one of the mechanisms used to keep certain genes switched off for decades in long-lived cell types such as neurons.

But what about those regions that aren’t screwed down tight, where there are genes that are switched on or have the potential to be switched on? This is where the histones really come into play. There is so much more to histones than just acting as a molecular reel for wrapping DNA around. If DNA methylation represents the semi-permanent additional notes on our script of Romeo and Juliet, histone modifications are the more tentative additions. They may be like pencil marks, that survive a few rounds of photocopying but eventually fade out. They may be even more transient, like Post-It notes, used very temporarily.

A substantial number of the breakthroughs in this field have come from the lab of Professor David Allis at Rockefeller University in New York. He’s a trim, neat, clean-shaven American who looks much younger than his 60 years and is exceptionally popular amongst his peers. Like many epigeneticists, he began his career in the field of developmental biology. Just like Adrian Bird, and John Gurdon before him, David Allis wears his stellar reputation in epigenetics very lightly. In a remarkable flurry of papers in 1996, he and his colleagues showed that histone proteins were chemically modified in cells, and that this modification increased expression of genes near a specific modified nucleosome[26].

The histone modification that David Allis identified was called acetylation. This is the addition of a chemical group called an acetyl, in this case to a specific amino acid named lysine on the floppy tail of one of the histones. Figure 4.4 shows the structures of lysine and acetyl-lysine, and we can again see that the modification is relatively small. Like DNA methylation, lysine acetylation is an epigenetic mechanism for altering gene expression which doesn’t change the underlying gene sequence.

^{Figure 4.4 The chemical structures of the amino acid lysine and its epigenetically modified form, acetyl-lysine. C: carbon; H: hydrogen; N: nitrogen; O: oxygen. For simplicity, some carbon atoms have not been explicitly shown, but are present where there is a junction of two lines.}

So back in 1996 there was a nice simple story. DNA methylation turned genes off and histone acetylation turned genes on. But gene expression is much more subtle than genes being either on or off. Gene expression is rarely an on-off toggle switch; it’s much more like the volume dial on a traditional radio. So perhaps it was unsurprising that there turned out to be more than one histone modification. In fact, more than 50 different epigenetic modifications to histone proteins have been identified since David Allis’s initial work, both by him and by a large number of other laboratories[27]. These modifications all alter gene expression but not always in the same way. Some histone modifications push gene expression up, others drive it down. The pattern of modifications is referred to as a histone code[28]. The problem that epigeneticists face is that this is a code that is extraordinarily difficult to read.