In the cell nucleus, the DNA is tightly wrapped around proteins called histones. In order for it to be read, this tight packing must loosen. Researchers have now visualized this process, known as nucleosome breathing, with the help of computer simulations at the atomic level. Their results provide new insights into the mechanisms that regulate gene expression. Accordingly, both the DNA sequence and the structure of the histones play an important role.
Every cell in our body contains DNA about two meters in length. So that it fits into the tiny cell nucleus, the long strand of genetic material is wrapped around histone proteins as if on coils. Eight histones with the DNA wrapped around them form a nucleosome. The entirety of these tiny structures in the cell nucleus is known as chromatin – the material that chromosomes are made of. However, as long as the DNA is tightly coiled in this way, it cannot be read. In order for it to serve as a blueprint for proteins, its packaging has to loosen up a little. To make this possible, the nucleosomes can move, rotate around their own axis and wrap and unfold. The DNA strand is sometimes wound more tightly, sometimes less tightly. The transitions from so-called closed to open chromatin resemble “breathing”. However, this process can hardly be made visible with experimental methods.
“Nanoscope” makes movements visible
A team led by Jan Huertas from the Hubrecht Institute in Utrecht in the Netherlands have now visualized this process with the help of computer simulations. To do this, the researchers used simulation methods that are so precise and detailed that the resulting images look as if they came from a high-resolution nanoscope. This “Computational Nanoscope” makes it possible for the first time to follow the movements of the genome molecules at the atomic level. In this way, Huertas and his colleagues created several short films that show the movement of the nucleosomes in real time and also make the typical dynamics of opening and closing visible – so-called nucleosome breathing.
“To be able to observe the breathing of nucleosomes in computer simulations is a great challenge. The fact that we can now visualize this is a decisive step towards simulating the entire spectrum of nucleosome dynamics – from breathing to unpacking, ”says Huerta’s colleague Vlad Cojocaru. A deeper insight into the detailed sequence of these processes helps to better understand an important aspect in the regulation of gene expression and possibly one day to use the findings therapeutically.
Histone tails regulate gene expression
Using their simulation, Huertas and his colleagues found out which factors influence nucleosome breathing. On the one hand, the DNA sequence plays an important role – i.e. the order in which the individual base components are arranged in the genome. On the other hand, the dynamics of the so-called histone tails are essential for this process. These are flexible regions in the histones that are involved in the regulation of gene expression. The histone tails can be modified by chemical deposits and thus influence which regions of the DNA are read and which are not.
How exactly the opening process works at the molecular level, however, was previously unknown. “Our simulations showed that two histone tails are responsible for keeping the nucleosome closed. The nucleosome was only able to open when these flexible tails moved away from certain regions of the DNA, ”describes Cojocaru. If the researchers removed the histone tails, the nucleosomes were able to open significantly wider. The basic pattern of movements, which is determined by the DNA sequence, remained.
Interplay between histones and DNA
“Active (open) and inactive (closed) chromatin contain different modifications of the histone tails,” explains Huertas. “The next step is to run simulations with such modifications. The atomic resolution of the simulations would enable us to determine exactly how each modification affects the nucleosomes and the chromatin dynamics. ”The researchers also want to shed more light on the interplay between the histones and the DNA sequence in the future.
While the current simulations only lasted a few microseconds, the observable time span could increase in the future. “With the further increase in computing power available around the world, we will soon be able to simulate milliseconds of the lifespan of a nucleosome and all of its atoms. In addition, we will then be able to routinely simulate multiple nucleosomes to study the effects of various modifications of histones on gene expression. This will enable unimagined insights into the mechanisms that regulate gene expression, ”says Cojocaru.
Source: Jan Huertas (Hubrecht Institute, Utrecht, Netherlands) et al., PLoS Computational Biology, doi: 10.1371 / journal.pcbi.1009013