Researchers at Sanford Burnham Prebys have published new findings that suggest understanding the three-dimensional shape of the genome in ependymoma, a deadly form of pediatric brain cancer, can reveal future drug targets. In their research, published in Nature Communications, the investigators used a combination of Hi-C with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression.
“The human genome is made up of many protein-coding genes and an even greater number of noncoding sections, which are all tightly packaged and coiled up to fit inside the tiny nucleus of a cell,” said Lukas Chavez, PhD, an assistant professor at Sanford Burnham Prebys, whose lab led the research. “We’re using cutting-edge technologies to look at the way that genome is packaged and coiled, which gives us a unique perspective on the mechanisms of gene regulation. This approach helps us understand the link between the shape of the genome and cancer.”
Brain and spinal cord tumors, including ependymomas are the most common cancer among children up to the age of 14 and are also the leading cause of pediatric cancer deaths. As Chavez noted, this form of cancer comes in a variety of genomic and molecular subtypes, each of which can determine how a patient will respond to treatment.
“The current standard-of-care treatment includes surgery followed by radiation, which bears the risk of long-term, therapy-induced neurological side effects as well as secondary cancers,” Chavez said. “New, targeted therapeutic options for ependymoma are desperately needed. If successful, our research will lead to new, effective medications to treat these dangerous cancers.”
To better understand ependymoma, the researchers studied the most aggressive forms of the disease and used the new combination of technologies, known as 3D genome mapping, to visualize how genes are organized within the cell nucleus. The technique looks to get a more realistic, real-world, representation of how genes occur naturally.
“Science has historically studied the genome in two dimensions, focusing on how genes are arranged in long, linear sequences,” said Chavez. “But the genome is a 3D object like anything else, and the way that genes are arranged in space makes a difference in how those genes are expressed in the body.”
Using this method, the investigators were able to study previously undiscovered loops in the genomes of ependymoma tumors. These loops change the way that genes are expressed, which in turn produces signals that help tumors grow.
“We’ve confirmed that configuration of these genes in the loops are essential for ependymoma tumors,” said Chavez. “This means that we now have a host of new candidate targets for treatments that we would never have been able to identify without this technology.”
Building on this work, the research team will now turn their focus to include other forms of pediatric cancers, since many of them also do not have many therapeutic choices.
“There are alarming numbers of tumors that we struggle to treat because we simply don’t know how they work from a biological standpoint,” concluded Chavez. “This work shows that there’s a lot more we still don’t know about the genomics of tumors, and unlocking these mysteries may be the key to finally overcoming these aggressive cancers.”
