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Researchers have identified unique three-dimensional features called TULIPs in the genome of posterior fossa group A ependymoma (PFA), a difficult-to-treat brain tumor diagnosed in very young children. The findings, published in Cell by a team of researchers from Baylor College of Medicine, Texas Children’s Hospital, McGill University and collaborating institutions, could lead to the development of new treatments.
“PFA ependymomas are deadly. Radiation therapy, the only currently available treatment, is not curative and can lead to serious developmental and cognitive problems,” said co-corresponding author Dr. Marco Galloassociate professor of pediatricshematology-oncology at Baylor and Texas Children’s Hospital. “One reason for the lack of progress in developing effective treatments for AFP is that most of these tumors lack clear genetic mutations that drive their growth. Without a clear therapeutic target against which we could design specific treatments, we took a different approach and studied the packaging of DNA inside the cell nucleus.”
Every cell in the body has about 2 meters of linear DNA that is stored in its nucleus in such a way that the cell can easily access the genes it uses most often while setting aside those it uses less frequently. This would be like organizing a closet with the most frequently used clothes in the front and the rarely worn ones in the back. To fit into the tiny nucleus, the long DNA molecules are folded, twisted, and looped, resulting in specific 3D conformations, some tighter, others more relaxed, that can ultimately help the cell express the genes it needs to do its job.
Very little is known about how pediatric brain tumor cells organize their genomes in 3D. “In this study, we used Hi-C technology to profile the 3D architecture of whole genomes of pediatric PFA ependymomas and compared them to those of different tumor types and non-malignant tissues,” said Dr. Michael D. Taylorco-senior author of the study and professor of pediatricsHematology-Oncology and Neurosurgery at Baylor and Texas Children’s. He also holds the Cyvia and Melvyn Wolff Chair in Pediatric Neuro-Oncology at Texas Children’s Cancer and Hematology Center. “We have discovered 3D genomic features specific to PFA ependymoma 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 specific regions of DNA that are very compact and therefore difficult to access, a sign that the cell does not use the genes in that region very often. “TULIPs also tend to interact with each other over very long distances. TULIPs on opposite ends of a chromosome can find ways to interact with surprising strength,” Gallo said. “TULIPs on different chromosomes can also converge and interact strongly with each other. We also found that the DNA in regions outside of TULIPs appears more relaxed. This is important because TULIPs are linked to the function of the cell.”
TULIPs carry a chemical tag, specifically a methyl group on histone H3K9, a DNA-associated protein. “We found that inhibition of H3K9 tagging in PFA patient-derived cultures leads to weaker interactions between TULIPs and an overall decrease in PFA ependymoma cell survival,” Gallo said. “Collectively, our data indicate that TULIP aggregation in the 3D nuclear space of PFA cells is dependent on maintaining robust levels of methylated histone H3K9, and that TULIP interactions are important for PFA cell viability, opening up potential new avenues for treatments.”
“The mechanism by which TULIPs induce cancer behavior is not fully understood,” Gallo said. “Our goal is to further study how TULIPs arise and influence the development of PFA ependymoma. The uniqueness of TULIPs in these high-risk tumors prompted us to explore treatment strategies directed against them to promote tumor elimination.”
Other contributors to this work include Michael J Johnston, John JY Lee, Bo Hu, Ana Nikolic, Elham Hasheminasabgorji, Audrey Baguette, Seungil Paik, Haifen Chen, Sachin Kumar, Carol CL Chen, Selin Jessa, Polina Balin, Vernon Fong, Melissa Zwaig, Antony MichealRaj, Xun Chen, Yanlin Zhang, Srinidhi Varadharajan, Pierre Billon, Nikoleta Juretic, Craig Daniels, Amulya Nageswara Rao, Caterina Giannini, Eric M Thompson, Miklos Garami, Peter Hauser, Timea Pocza, Young Shin Ra, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Ji Yeoun Lee, Wieslawa Grajkowska, Marta Perek-Polnik, Sameer Agnihotri, Stephen Mack, Benjamin Ellezam, Alex Weil, Jeremy Rich, Guillaume Bourque, Jennifer A Chan, V Wee Yong, Mathieu Lupien, Jiannis Ragoussis, Claudia Kleinman, Jacek Majewski, Mathieu Blanchette and Nada Jabado. Find the authors’ affiliations in the publication.
This work was supported by a Large-Scale Applied Research Project Grant from Génome Québec, Genome Canada, the Government of Canada, and the Ministère de l’Économie et de l’Innovation du Québec, with support from the Ontario Research Fund through funding provided by the Government of Ontario. Additional support was provided by Brain Canada through the Canada Brain Research Fund, Health Canada, and the Azrieli Foundation through an Azrieli Future Leader in Canadian Brain Research Grant, Canadian Institutes of Health Research (CIHR) Project Grants (PJT-156278 and PJT-173475), a CIHR Postdoctoral Fellowship, and a Canada Research Chair and Texas Children’s Hospital.
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