Estrogens, the primary female sex hormones that also play roles in men, are known to regulate hundreds of genes and are involved in many bodily processes. A new study led by the Spanish National Cancer Research Centre (CNIO) has revealed that the way DNA twists or supercoils is a key factor in how cells respond to estrogens.
"We have discovered that the way the DNA molecule coils and uncoils, its topology, is key for cells to respond to estrogens," said Felipe Cortés, a CNIO researcher and co-lead author of the study published in Science Advances.
The research highlights that within cell nuclei, DNA constantly changes its configuration through twisting and unfolding. This dynamic contributes to gene activation or deactivation. The study’s authors include Gonzalo Millán-Zambrano from CABIMER at the University of Seville-CSIC-University Pablo de Olavide, and José Terrón Bautista, now at Helmholtz Zentrum in Munich.
DNA contains genetic information as sequences of chemical components represented by A, T, C, and G. While all cells share this sequence, different cell types activate different genes at various times. Understanding how cells control which genes they express remains a central question in biology.
Recent advances have shown that genome information is encoded not just linearly but also in three dimensions. The folding of DNA within the tiny nucleus allows distant regions to come into contact physically—a process essential for activating or deactivating genes. Errors in this folding can lead to diseases such as cancer.
"We are starting to understand how this three-dimensional organisation influences gene activity," Cortés noted.
Estrogens function as chemical signals modifying expression of numerous genes linked with reproduction, metabolism, cell growth, differentiation and survival. The CNIO-led study found that these functions depend on physical changes in DNA folding mediated by topoisomerase enzymes.
"We found that, in the presence of estrogens, topoisomerases modify the coiling of DNA, thus controlling the activation of target genes," explained Cortés.
Topoisomerases change DNA’s supercoiling—when a molecule twists upon itself much like an old telephone cord relieves tension through spontaneous supercoiling. "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 estrogen-responsive genes," said Cortés.
The researchers concluded: "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...the cell actively generates and modulates those tensions to promote contacts that stimulate gene activation."
While not directly related to treatment yet, these findings may impact cancer therapies since many breast cancers require estrogens for growth and current treatments often block hormonal signals or use topoisomerase inhibitors. "Our results show that the way DNA is coiled directly influences how cells respond to estrogens. This suggests that hormonal signalling and topoisomerases...are actually functionally connected, which could help explain resistance mechanisms and contribute to...more personalised and effective therapies," said Cortés.
