TULIPs decorate the three-dimensional genome of PFA ependymoma.

in Cell by Michael J Johnston, John J Y Lee, Bo Hu, Ana Nikolic, Elham Hasheminasabgorji, Audrey Baguette, Seungil Paik, Haifen Chen, Sachin Kumar, Carol C L Chen, Selin Jessa, Polina Balin, Vernon Fong, Melissa Zwaig, Kulandaimanuvel 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, Nada Jabado, Michael D Taylor, Marco Gallo

TLDR

  • The study looked at the way the genes in a type of brain cancer called PFA ependymoma are arranged in 3D space. They found that PFA has a special feature called TULIPs, which are regions that interact with each other in the 3D space even though they are separated by great distances along the linear genome. The study also found that the formation of TULIPs is controlled by a protein called EZHIP. This information could help researchers find new ways to treat PFA ependymoma.

Abstract

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in the 3D nuclear space with surprising strength. TULIPs occur in all PFA samples and recur at predictable genomic coordinates, and their formation is induced by expression of EZHIP. The universality of TULIPs across PFA samples suggests a conservation of molecular principles that could be exploited therapeutically.

Overview

  • The study aims to investigate the 3D genome of Posterior fossa group A (PFA) ependymoma, a lethal brain cancer in infants and young children. The study tests the hypothesis that PFA has characteristic features in its 3D genome that could be exploited therapeutically. The methodology used for the experiment includes reconstructing 3D genomes from diverse childhood tumor types and identifying a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. The study also identifies a remarkable feature exclusively present in PFA, type B ultra long-range interactions in PFAs (TULIPs), which occur in all PFA samples and recur at predictable genomic coordinates. The primary objective of the study is to understand the molecular principles underlying TULIPs and their potential therapeutic implications.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, specifically the reconstruction of 3D genomes from diverse childhood tumor types and the identification of a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. The study identifies a remarkable feature exclusively present in PFA, type B ultra long-range interactions in PFAs (TULIPs), which occur in all PFA samples and recur at predictable genomic coordinates. The study also finds that the formation of TULIPs is induced by expression of EZHIP. The key findings of the study are that TULIPs are a universal feature across PFA samples and could be exploited therapeutically.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they suggest a conservation of molecular principles that could be exploited therapeutically. The study identifies a remarkable feature exclusively present in PFA, type B ultra long-range interactions in PFAs (TULIPs), which occur in all PFA samples and recur at predictable genomic coordinates. The study also finds that the formation of TULIPs is induced by expression of EZHIP. The limitations of the study include the small sample size and the need for further research to validate the findings. Future research directions could include exploring the role of TULIPs in PFA ependymoma pathogenesis and identifying potential therapeutic targets for TULIP-based therapies.
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