Dr Erika Mancini is interested in the role of chromatin in the regulation of gene transcription. All our cells contain the same set of genes, but only some of them are transcribed at any point in a particular tissue. Regulation of gene transcription is strongly linked to chromatin, physical packaging of the DNA within the nucleus.
Chromatin plays an important role in the regulation of gene expression. The movement of nucleosomes, packing and unpacking DNA, is governed by chromatin remodelling ATPases. Malfunctions in the regulation of chromatin structure often leads to complex multi-system diseases and cancer, notably leukemia.
Ultimately, medical research must translate into improved treatments for patients. At the Nuffield Department of Medicine, our researchers collaborate to develop better health care, improved quality of life, and enhanced preventative measures for all patients. Our findings in the laboratory are translated into changes in clinical practice, from bench to bedside.
EM: Thanks for asking a very interesting question. Many people will have heard of DNA but perhaps not of chromatin. Each cell in our body contains about 2 metres of linear DNA which looks a bit like this. It's very thin, but it's very long. This DNA will be divided into little segments, in fact 30,000, which represent our genes. Genes define who we are, how we work and of course malfunctioning of genes, misactivation of genes can lead to a number of diseases and cancer. There is a very big problem here. We need to be able to fit about 2 metres of DNA inside the nucleus of a cell, and a nucleus of a cell has a diameter of about 5 microns. So there's an amazing compactation that needs to be going on in order to put this DNA inside our cells. Our cells use a very clever trick, the spool trick. They just wrap the DNA around a complex of proteins known as histones which look a bit like round spools, essentially. By doing this they achieve a compactation of about 20,000 times and of course there's not only one histone, there will be a collection of them so this is pretty much what chromosomes look like in our body.
Q: So why is this important?
EM: Well as with all storage spaces there are advantages and disadvantages, if you want. If a gene needs to be activated because it's required in a certain moment in time of course you will need to take that little piece of string and find that bit inside the string which encodes for that gene. And if it's in this state it's going to be difficult to find. So, there's a problem. On the other hand there might be an advantage to this chromatin because not every gene has to be active at the same place, at the same time. For example in our brain, there are a number of genes which are brain specific and they will not be necessary for example in our liver where other genes are important and brain genes are not very important, in fact they might be deleterious to be expressed in the brain. So there's a constant need for the chromatin to be open and closed and this is a very important mechanism. There is a whole new layer of complexity in our genetic code which has been named the epigenetic code. It's a code which sits on top of our genetic code and regulates further our genetic code.
Q: So is that what we would call regulating chromatin?
EM: Exactly yes, chromatin regulation.
Q: Why does your line of research matter? Why should we put money into it?
EM: Well chromatin compactation is achieved by a number of factors and one of them is chromatin remodeling ATPases which is my line of research. Chromatin remodeling ATPases essentially do the work of opening and closing the chromatin, and as you might imagine because of their fundamental role in the working of our genes they are very much essential, and malfunctioning of these proteins is the main cause of lethality in embryos and they lead in the case of mutations to a number of diseases and cancers. So there's a huge drive at the moment to put money into epigenetics and chromatin remodeling research in the hope that we might translate it into important therapeutic avenues.
Q: Is that how you feel your research will fit into translational research within this department?
EM: My research somehow complements what is done in the department. There is a lot of expertise in genetics so my work in epigenetics and chromatin remodeling is a sort of complement. Specifically there are a number of lines in my research which translate directly into some translational medicine. For example, one of my interests is in the proteins, the chromatin remodeling ATPases, which are important for the regulation of blood development - red cells, white cells. And we all know that misregulation in this gene process of blood differentiation is important for leukemia, so I'm looking into how chromatin remodeling ATPases are important for initiation of leukemia for example. There is a number of congenital heart diseases which now, it appears, could be caused by malfunctioning of chromatin remodeling ATPases. So I'm hopeful that some of the insights from my research might translate in the future into therapeutic avenues.