DNA winds around histones….Credit: Max Planck Society

Most everybody knows that DNA is the carrier of the genetic code, the instructions for how life reproduces, grows, and maintains. Cell biologists have long known that DNA comes with a very complex packaging material, proteins called histones, which help the 2 meter (6 foot) strand of DNA (in humans) fold into a tiny ball that will fit in the nucleus in each and every cell in the body.

During the 1990’s, as scientsts had more sophisticated genetic surveillance systems, evidence began to accumulate that histones were more than packing material. In fact, it began to look like histones could act as gatekeepers to the DNA, determining which portions of the DNA were available for protein expression. In short, histones play a role in expressing the genetic code and may have a code of their own – the histone code.

There is more to it than that. Histones can be modified, and those modifications can be reproduced (inherited) every time a cell replicates. This is part of what is called epigenetics, a rapidly emerging field of biology, which has been given many definitions but generally is the study of inherited changes in gene expression (for example, changes in physical appearance) other than caused by changes in DNA. It’s becoming apparent that a very large percentage of the way DNA becomes ‘expressed’ – how DNA provides instructions to create proteins – is guided by epigenetic factors. Of these factors, histones appear to be among the most important.

Yet it can be said that when it comes to gene expression not much is known about histones. There is no ‘sequencing of the histone code’ like there is for DNA. In fact, there is little cataloging of histones other than very broad categories (core: H2A, H2B, H3, H4; linker: H1, H5). To address this lack of knowledge, scientists at the Max Planck Institute for Biophysical Chemistry (Göttingen, Germany) decided that ‘cracking the histone code’ required new techniques that make studying the activity of specific histones much more accessible.

Their approach involves that old friend of the genetics lab, drosophila melanogaster a.k.a. the fruit fly. The key to the technique was identifying the genes in the genome of the fruit fly that produce histones and then removing them, all of them. When this is done, the cells with altered DNA produce a copy of the DNA at the start of cell replication, but go no further. The cells die. In a way, this might be called a blank slate. Then the scientists began adding copies of modified histone genes (transgenes) to cells with all the original histone genes removed, and observing the changes in histone expression (protein creation). For example, they learned that with twelve copies of the histone gene cluster a fly could survive and reproduce.

With further sophistication, the switcheroo technique can be used to produce many kinds of variations in histones, and correspondingly in how the histones interact with the DNA. In time, this will hopefully make it possible to solve the ‘histone code.’ The research probably needs to go much further into the biochemistry involved.

It’s difficult to say how important histones will be in the overall picture of gene expression. At this point, their role is yet another surprise in what seems to be a massive complementary environment of DNA. Histones, like other epigenetic mechanisms, are much more important than originally thought. They are, among other things, the interface between the cell, the real world, and DNA. Put another way, when the real world does something to the cell – like put it under stress – it is the job of the histones to react and alter the way DNA is expressed in order to deal with the stress.

This is obviously an important role, and science is only beginning to understand how it works.

[Source: A genetic system to assess in vivo the functions of histones and histone modifications in higher eukaryotes]