Estrogen is known as an important hormone, and it can control many cellular and bodily functions by regulating the activity of hundreds of genes. Scientists have now learned more about how estrogen can do that, and by viewing cells at high magnification, they have seen that estrogen’s influence relies on how DNA is twisted and coiled. The findings have been reported in Science Advances.
"We have discovered that the way the DNA molecule coils and uncoils–its topology, is key for cells to respond to estrogens," said co-first study author Felipe Cortés, the head of the DNA Topology and Breaks group at the Spanish National Cancer Research Center (CNIO). “When estrogens 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.”
The human genome is very large, so DNA must be carefully compacted so that it will fit inside the nucleus of cells. Yet different parts of it have to remain physically accessible to facilitate gene expression. So the structure of DNA changes often, and it can twist, coil, supercoil, and untwist so that various active portions are available to the cellular machinery that expresses genes. Gene expression is fundamental to organisms. Cells obtain their identity and perform their functions through the expression of specific genes.
So DNA has to be properly compacted, coiled, or unwound so that the right genes can be expressed at the right times. "We are starting to understand how this three-dimensional organization influences gene activity," Cortés noted.
This study has shown that estrogen’s ability to modify the activity of hundreds of genes depends on the physical structure of DNA, which is mediated by enzymes known as topoisomerases. These enzymes can alter supercoiled DNA, so that different parts of the DNA sequence can come together. Contact between these regions is crucial to the expression of genes that are responsive to estrogen.
"We found that, in the presence of estrogens, topoisomerases modify the coiling of DNA, thus controlling the activation of target genes," said Cortes.
"Our results show that the way DNA is coiled directly influences how cells respond to estrogens. This suggests that hormonal signaling and topoisomerases, traditionally considered independent therapeutic targets, are actually functionally connected, which could help explain resistance mechanisms and contribute to the design of more personalized and effective therapies.”
Sources: The Spanish National Cancer Research Centre, Science Advances
