Oestrogens, the main female sex hormone, although they also perform some functions in men, are involved in a myriad of processes, which is why the body changes so much during menopause. This is because oestrogens regulate hundreds of genes. A study led by the Spanish National Cancer Research Centre (CNIO) now shows how they do it, by looking right into the core of the cell. Researchers have found that the action of oestrogens depends on a physical property of DNA: its ability to twist or supercoil.
"We have discovered that the way the DNA molecule coils and uncoils, its topology, is key for cells to respond to oestrogens," explains CNIO researcher Felipe Cortés, co-lead author of the study, which is published in Science Advances .
"When oestrogens arrive, enzymes called topoisomerases regulate the coiling of DNA, thereby controlling the activation of the genes necessary for the cell to respond to the hormones," says Cortés, head of the DNA Topology and Breaks group at CNIO.
These are processes that occur in minutes. Within our cells, in the nucleus, the DNA molecule is constantly changing its configuration, twisting and unfolding to a greater or lesser extent, and this contributes to the activation or deactivation of genes.
The authors of the paper now published in Science Advances include Gonzalo Millán-Zambrano from the Andalusian Centre for Molecular Biology and Regenerative Medicine ( CABIMER ) at the University of Seville-CSIC-University Pablo de Olavide, and José Terrón Bautista, now a postdoctoral researcher at the Helmholtz Zentrum in Munich, Germany.
How to activate the right gene at the right time
The genetic information encoded in each of our DNA – our genome – is made up of a sequence of different chemical components (usually represented as letters: A, T, C, G). The DNA sequence is the same in all the cells of an organism, but each type of cell reads different parts of the DNA molecule – the genes – at different times, which is why there are different tissues and organs.
In other words, each cell carefully controls which genes it reads – 'activates' or 'expresses' – at any given moment. The question of how it does this is absolutely crucial in biology, and it is the focus of the recently published study.
One of the main paradigm shifts in this area stems from the recent finding that the information in the genome is encoded in three dimensions. In other words, the 3D shape of the genome influences which genes are expressed at what time.
The third dimension of the genome
The cell nucleus, which measures thousandths of a millimetre in diameter, houses our DNA, which, when unwound, measures two metres in the case of humans. DNA is therefore densely folded, but not like tangled wires; it follows a very strict order. This makes it possible for linearly distant regions of DNA to come into contact, and it is this physical proximity that activates and deactivates genes. The proper folding of DNA is so important that if there are errors, diseases, including cancer, can appear.
Understanding this process is a rapidly advancing area of research. The folding of DNA determines how the cell reads and interprets the information in the genome. "We are starting to understand how this three-dimensional organisation influences gene activity," Cortés points out.
Oestrogens, gene activation and DNA supercoiling
Oestrogens act as chemical signals that modify the expression of hundreds of genes related to reproduction, metabolism, cell growth, differentiation and survival.
The new study in Science Advances shows that this function of oestrogens directly depends on physical changes in the folding of DNA, changes mediated by topoisomerase enzymes.
"We found that, in the presence of oestrogens, topoisomerases modify the coiling of DNA, thus controlling the activation of target genes," Cortes explains.
Specifically, topoisomerases modify the supercoiling of DNA, the phenomenon by which the molecule twists upon itself in the way that a cable from an old corded telephone, after a certain number of turns, spontaneously supercoils to relieve the physical tension of the torsion.
Enzymes that regulate supercoiling to control gene expression
"Changes in supercoiling induced by topoisomerases affect the three-dimensional organisation of the genome and therefore how different regulatory regions touch each other; these contacts are essential for activating oestrogen-responsive genes," says the researcher from CNIO.
In short, "we have shown that the way DNA twists is a layer of gene expression regulation that had previously gone unnoticed. Until now, it was thought that topoisomerases simply removed DNA tensions; our work shows that, in the response to oestrogens at least, the opposite occurs: the cell actively generates and modulates those tensions to promote contacts that stimulate gene activation."
Relationship with breast cancer
The study is related, although not immediately, to the treatment of cancer. Many breast cancers need oestrogens to grow, and standard treatments work by blocking that hormonal signal. Furthermore, topoisomerase inhibitors, which directly affect the topology of DNA, are also used in the treatment of various tumours, sometimes in combination with hormone therapies.
"Our results show that the way DNA is coiled directly influences how cells respond to oestrogens. This suggests that hormonal signalling and topoisomerases, traditionally considered independent therapeutic targets, are actually functionally connected, which could help explain resistance mechanisms and contribute to the design of more personalised and effective therapies," Cortés indicates.
About the National Cancer Research Centre (CNIO)
The National Cancer Research Centre (CNIO) is a public research centre under the Department of Science, Innovation and Universities. It is the largest cancer research centre in Spain and one of the most important in Europe. It includes around five hundred scientists, along with support staff, who are working to improve the prevention, diagnosis and treatment of cancer.
