Researchers have identified unique 3-dimensional features called TULIPs in the genome of posterior fossa group A (PFA) ependymoma, a challenging brain tumor diagnosed in very young children. The findings, published in Cell by a team from Baylor College of Medicine, Texas Children’s Hospital, McGill University, and collaborating institutions, could pave the way for new treatments.
“PFA ependymomas are lethal. Radiation therapy, the only treatment currently available, is not curative and can cause serious developmental and cognitive issues,” said co-corresponding author Dr. Marco Gallo, associate professor of pediatrics at Baylor and Texas Children’s. “One of the reasons for the little progress in the development of effective treatments for PFA is that most of these tumors lack clear genetic mutations driving their growth. Without a clear therapeutic target against which we could design specific treatments, we took another approach and investigated the DNA packaging inside the nucleus of the cell.”
Every cell in the body contains about 6.6 feet (2 meters) of linear DNA stored in its nucleus in an organized manner to facilitate gene access. This organization results from folding, twisting, and looping long DNA molecules into specific 3D conformations.
“In this study, we used Hi-C technology to profile the 3D architecture of entire genomes of pediatric PFA ependymomas and compared them with those of different tumor types and non-malignant tissues,” said Dr. Michael D. Taylor, co-senior author and professor at Baylor and Texas Children’s Cancer Center. “We discovered PFA ependymoma-specific 3D genome features that recur at predictable genomic locations. Interestingly, these features are not present in other types of pediatric brain cancer. We call them TULIPs, which stands for Type B Ultra-Long Interactions in PFAs.”
TULIPs are tightly compacted regions indicating infrequent gene use within those areas. “TULIPs also tend to interact with each other over very long distances,” Gallo noted. “TULIPs on different chromosomes can also converge and strongly interact with each other.” These interactions are significant as they relate to cell function.
The research further revealed that TULIPs carry a methyl group tag on histone H3K9 associated with DNA. “Inhibiting this tagging in PFA patient-derived cultures leads to weaker interactions between TULIPs and an overall decrease in PFA ependymoma cell survival,” Gallo explained.
“The mechanism by which TULIPs mediate cancerous behavior is not entirely understood,” Gallo added. The researchers aim to explore how TULIPs influence PFA ependymoma development further.
Other contributors include Michael J Johnston, John JY Lee, Bo Hu, Ana Nikolic, Elham Hasheminasabgorji among others from various institutions globally.
This work received support from Génome Quebec, Genome Canada among others through several grants including those provided by Health Canada and Canadian Institutes of Health Research (CIHR).
