The genome is a real thing, and this is something we strongly need to keep in mind. The development of bioinformatics has brought us to make a very important, but still bold simplification. A strong focus on sequences, and the information they bear, allowed us to understand how genes determine the structure and function of proteins, and is driving the work of anyone focusing on the interpretation of non-coding elements, in the restless seek of what someone calls the regulatory code. Basically, we took the object shown in the picture above, and transformed it in flat files that underwent to the application of information theory. Beyond the obvious and widely discussed advantages, this approach may have the potential to be misleading. The genome is a physical body, with its physical and chemical features. And as epigenetics is putting the protein- DNA interaction under the spotlight, many studies are underlying that the functioning, the regulation, and thus the evolution of the genome need to be explored considering the genome as what it really is: a complex three-dimensional object.
I really enjoyed the read of a paper dating back to the 2011, authored by Johan H. Gibcus and Job Dekker from the University of Massachusetts. Entitled The Hierarchy of the 3D Genome, the article provides an effective point of view on how radically the DNA folding affects the genome regulation. Recent innovation in probing interphase chromatin folding are in fact providing new insights into the spatial organisation of genomes and its role in gene regulation. In fact, a paper by Marc M. Renom (CNAG- Barcelona) on PlOS, that is aimed at explaining the state of the art of computational methods for genome folding analysis, argues that after the advent of fluorescent in situ hybridisation imaging and chromosome conformation capture methods, the availability of experimental data on genome three-dimensional organisation has dramatically increased. This information has been recently made available in the 3D Genome Database (3DGD), that is the result of the work of a Chinese team, and gathers the Hi-C chromatin conformation capture data of four species (human, mouse, drosophila and yeast).
Of course, many results proving a role of genome folding in gene regulation and phenotype determination are leaping off. As already discussed in this blog, researchers from McGill University in Canada have proven that leukaemia types can be classified with chromatin conformation data. Under an evolutionary point of view, we could have a look to this paper published on Nature in 2012, in which specific chromatin- interaction domains, defined as topological domains, are found to be conserved over the time and in different species.
Beyond any consideration, and further discussion, we could assume that a change in the approach we adopt in genome studies is needed. These findings suggest that a level of major complexity affects genome regulation, and this cannot definitely be ignored. In evolution, we should ask how the chromatin structures have established over the years, and understand their meaning in phenotype and adaptation. Of particular interest, would be the role of non-coding sequences, the so-called junk (and not so) junk DNA, that has been found in many topological domains and may have a role. Ultimately, as we assign a function of three dimensional structure for DNA, as we did in proteins, we should investigate the relationship between the sequence and the structure, and the information exchange between proteins and DNA in protein binding. It seems that not everything is clear about the nature of the information in biological macromolecules, but that’s all but a novelty.