A fundamental organizing principle in cellular biochemistry is the formation of droplets through a process of liquid-liquid phase separation.
A new study from researchers at the University of Virginia (UVA) School of Medicine offers evidence that these liquid condensates regulate the structure of chromatin and the expression of genes in time and space. And when these condensates fail to form properly, it can result in cancer. These findings are reported in the Nature article titled, “UTX condensation underlies its tumor-suppressive activity.”
Hao Jiang, PhD, associate professor of biochemistry and molecular genetics at the UVA Cancer Center, and his collaborators focused on a gene on the X chromosome called UTX that is frequently mutated in human cancers. The gene encodes an enzyme that removes methyl groups from a DNA scaffolding protein called histone H3K27 that when methylated is known for shutting down transcription. But UTX’s enzymatic activity is dispensable in its role as a tumor suppressor or a developmental regulator, leaving a question mark on its molecular function.
“How UTX inactivation causes human cancers remained elusive, as we did not know its key molecular activity that is critical for tumor suppression, posing a barrier to cancer therapies targeting UTX-related pathways,” said Jiang. “Our work largely solved this mystery. Moreover, it suggests that disruption or alterations of these droplets can profoundly affect how our cells fight cancer. Forming proper droplets is likely to be a fundamental mechanism that maintains cellular health, and we are just beginning to understand.”
In their Nature paper, Jiang and colleagues showed that UTX’s biological function is to form tiny droplets in cells (liquid-liquid phase separation). This underlines its function as a chromatin regulator and tumor suppressor. A mutation in the gene throws a wrench in this basic machinery, increasing the risk for cancer.
“We are very interested in how the condensate properties of UTX are regulated in cells and how other proteins may control cancer through forming droplets,” Jiang said. “These studies will likely open up new approaches to cancer treatment by regulating these droplets.”
The study reveals an important and largely unrecognized way our bodies keep us safe from cancer. Through directing the formation of these droplets in cells, UTX prevents tumorigenesis. These droplets condense from materials in cells like water droplets condense on cold glass.
Once the droplets have formed, important biological processes can take place. In addition to suppressing the growth of cancer, these droplets direct the development and differentiation of embryonic stem cells that can form any cell type (pluripotent).
The authors uncovered that the role of these condensates in suppressing tumor is based on their ability to control the “optimal activity” of the genetic material contained in our chromatin. The droplets, they noted, “ensure efficient and correct chromatin modifications and interactions to orchestrate a proper tumor-suppressive transcriptional program.”
A disordered region at the core of the UTX protein helps in forming the liquid droplets, the authors showed. Mutations that abolish this region of UTX are most frequently linked to cancer. Through deletion, mutagenesis, and replacement assays the researchers show this intrinsically disordered region plays a pivotal role in droplet formation, tumor suppression, and embryonic stem cell differentiation.
Moreover, through in vitro assays in engineered stem cells, the team revealed UTX recruits an enzyme that methylates histones to the same droplets, thereby enriching histone methylation.
UTX’s impact is not limited to a single site in the genome. The enzyme regulates genome-wide histone modifications and high-order chromatin interactions through the formation of these droplets.
It is not simply the formation of these liquid condensates but the state of their physical nature and molecular dynamicity that determine their efficacy in preventing cancer. The authors showed UTX’s counterpart on the male Y chromosome, an allele called UTY, forms condensates that are less dynamic, exhibiting physical properties that are less liquid and more like a solid. This makes the male droplets less effective in suppressing the formation of tumors and may be partly responsible for the increased incidence of cancer in men compared to women—a widely observed and yet unexplained phenomenon.