In this interview, Pablo Dans, an expert on the structure of DNA, will lead us in an amazing journey inside the cell nucleus to discover some of the roles of the non-coding regions. Pablo, a postdoctoral researcher in the group of Molecular Modelling and Bioinformatics at IRB Barcelona (Institute for Research in Biomedicine), is the author of several high-impact publications, most of them regarding the nucleic acids. His long-standing career has begun in Uruguay where he received his doctorate in chemistry from the University of the Republic (Montevideo, Uruguay).
M: Pablo, what are you currently working on?
P: Right now I’m working on several lines of research related to nucleic acids such as DNA and RNA. I got my PhD a few years ago and I did all my postdoctoral studies on DNA and RNA… Scientists sometimes change subject during their career, but I’m still obsessed with the same one. My work is mainly theoretical: I spend most of my time developing chemical models based on equations and laws of physics to represent DNA and RNA. These models allow us to reproduce their flexibility and their movements and to study their relationship with the biological environment – all essential features to understand their function.
M: You study the DNA from a structural point of view; what does it mean?
P: “Structural level” has many meanings, but it is generally associated with how the atoms are connected to form molecules. At first glance, DNA looks like a very simple molecule, composed of 4 building blocks, the nucleotides (A, C, G and T), and a very regular shape, the double helix. However, DNA is involved in a large number of biological processes covering a wide range of time and space. Let me explain it with an example: to study how solar radiation causes mutations in our DNA, we have to analyze DNA at the atomic scale and with an incredible accuracy. However, to study ageing in humans we have to analyze what happens to the entire genetic material for months or years. Similarly in our research group we study the structure of nucleic acids at different levels: looking to their atoms and using larger models to simulate their macro-structure and their organization inside the cell.
M: DNA shows different levels of organization and complexity: do non-coding regions have a role in that?
P: Of course. In 2012 a large team of scientists published the results of an important project, ENCODE, which had the goal to understand how the genetic information is regulated. For example: which regions do become a protein? when? All this accessory but crucial information is hidden inside the same code. Here an impressive fact: even though only 2% of the DNA encodes for proteins, at least 10% is made of regulatory regions. Five times more regulatory elements rather than genes that code for proteins!
Indeed a large variety of regulatory mechanisms exists. Some non-coding DNA regions regulate a nearby gene (cis-regulatory-elements) while others regulate genes in an area located far away (trans-regulatory-elements). In the case of trans-elements, a complex spatial coordination is required to bring all the related DNA regions in the same area of the cell nucleus in order to be all available at a given time.
M: And how is DNA structurally organized within the nucleus?
P: Inside the cellular nucleus the DNA double helix is compacted – with some regions more compacted and other still accessible. Many proteins and non-coding regions are involved in keeping such compactions. Recent results have shown that DNA is organized in territories too, which arise from the relocation of some chromosomes in specific areas of the nucleus. Luckily today there are experimental techniques to obtain detailed maps of the interactions occurring between the DNA filaments inside the nucleus. For example, we can detect the regions of the chromosome 1 that are in contact with regions of the chromosome 4. In our group, we are currently working on some models to interpret these experimental data, which will allow us to understand how chromosomes interact with each other and later to model their behavior.
M: I presume that these interactions are not random, right?
P: Absolutely not. They depend on the cellular type, its stage of development, the signals from outside and probably thousands of other factors that are not yet known. Despite the immensity of variables in play, these processes are finely regulated as in the best swiss watch, allowing only very specific actions that help regulatory elements (which are non-coding parts) and genes to come together in areas where are also available the proteins necessary for the proper reading and processing of DNA. This mechanism contributes to determining how the genetic material controls the cellular processes.
M: Have you ever studied a peculiar non-coding region?
Q: I have worked in the past on the telomeric regions, which are the endpoints of the chromosomes. Telomeres have a peculiar quadruple helix structure, but their most interesting feature, from my point of view, is that they are very rich in guanine (G). The guanines are a type of nucleotides that are capable of absorbing the oxidative damage of DNA caused by radiation or chemical agents. A damage in a coding region of DNA (which could lead to defective mutated proteins, or even cut the DNA strand) can travel large distances, using DNA as a molecular wire, to relocate in the guanines of telomeric areas. Thus, when a damage occurs in a coding region, it might be transferred to a noncoding region, such as telomeres, where the consequences are less hazardous.
M: If you could sequence your entire genome, what would you like to know?
P: It doesn’t sound very appealing to me to discover if I have a propensity for a disease or not – I prefer to stay ignorant. I find more interesting the tracking of your origins. There are some videos on youtube about it and some people might have a lot of surprises – some nice, some less, according to the prejudices of each one. Applications in biomedicine, especially the prenatal ones, are also powerful. I think that, if I had the opportunity to do these tests for genetic compatibility between couples, before having my children – who are thankfully both healthy and wonderful, I would have used that.