TULIPs decorate the three-dimensional genome of PFA ependymoma

Michael J Johnston¹, John J Y Lee², Bo Hu³, Ana Nikolic⁴, Elham Hasheminasabgorji⁴, Audrey Baguette⁵, Seungil Paik¹, Haifen Chen⁶, Sachin Kumar⁷, Carol C L Chen⁶, Selin Jessa⁵, Polina Balin², Vernon Fong², Melissa Zwaig⁶, Kulandaimanuvel Antony Michealraj⁷, Xun Chen⁸, Yanlin Zhang⁹, Srinidhi Varadharajan¹⁰, Pierre Billon¹¹, Nikoleta Juretic¹², Craig Daniels¹³, Amulya Nageswara Rao¹⁴, Caterina Giannini¹⁴, Eric M Thompson¹⁵, Miklos Garami¹⁶, Peter Hauser¹⁶, Timea Pocza¹⁶, Young Shin Ra¹⁷, Byung-Kyu Cho¹⁸, Seung-Ki Kim¹⁸, Kyu-Chang Wang¹⁸, Ji Yeoun Lee¹⁸, Wieslawa Grajkowska¹⁹, Marta Perek-Polnik²⁰, Sameer Agnihotri²¹, Stephen Mack¹⁰, Benjamin Ellezam²², Alex Weil²³, Jeremy Rich²⁴, Guillaume Bourque²⁵, Jennifer A Chan²⁶, V Wee Yong²⁷, Mathieu Lupien²⁸, Jiannis Ragoussis²⁵, Claudia Kleinman²⁹, Jacek Majewski⁶, Mathieu Blanchette³⁰, Nada Jabado³¹, Michael D Taylor³², Marco Gallo³³

Affiliations

¹ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
² The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada.
³ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁴ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
⁵ Quantitative Life Sciences, McGill University, Montreal, QC H3A 1B9, Canada.
⁶ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada.
⁷ Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁸ Department of Anatomy and Cell Biology, Kyoto University, Kyoto 606-8501, Japan.
⁹ School of Computer Science, McGill University, Montreal, QC H3A 2A7, Canada.
¹⁰ Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
¹¹ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
¹² Department of Pediatrics, McGill University and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
¹³ The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
¹⁴ Pediatric Hematology-Oncology, Mayo Clinic, Rochester, MN 55905, USA.
¹⁵ Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA.
¹⁶ Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary.
¹⁷ Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul 05505, South Korea.
¹⁸ Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 30322, South Korea.
¹⁹ Department of Pathology, The Children's Memorial Health Institute, University of Warsaw, 04-730 Warsaw, Poland.
²⁰ Department of Oncology, The Children's Memorial Health Institute, University of Warsaw, 04-730 Warsaw, Poland.
²¹ Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States of America.
²² Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, QC H3T 1C5, Canada.
²³ Department of Pediatric Neurosurgery, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, QC H3T 1C5, Canada.
²⁴ University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15213, USA; Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
²⁵ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada; McGill Genome Centre, Montreal, QC H3A 0G1, Canada.
²⁶ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
²⁷ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
²⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
²⁹ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
³⁰ Quantitative Life Sciences, McGill University, Montreal, QC H3A 1B9, Canada; School of Computer Science, McGill University, Montreal, QC H3A 2A7, Canada.
³¹ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada; Department of Pediatrics, McGill University and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC H3A 3J1, Canada. Electronic address: nada.jabado@mcgill.ca.
³² The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Cancer and Hematology Center, Texas Children's Hospital, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: michael.taylor@bcm.edu.
³³ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Cancer and Hematology Center, Texas Children's Hospital, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: marco.gallo@bcm.edu.

PMID: 38986619
DOI: 10.1016/j.cell.2024.06.023

Free article

TULIPs decorate the three-dimensional genome of PFA ependymoma

Michael J Johnston et al. Cell. 2024.

Free article

. 2024 Jul 4:S0092-8674(24)00697-4.

doi: 10.1016/j.cell.2024.06.023. Online ahead of print.

Authors

Affiliations

¹ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
² The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada.
³ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁴ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
⁵ Quantitative Life Sciences, McGill University, Montreal, QC H3A 1B9, Canada.
⁶ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada.
⁷ Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁸ Department of Anatomy and Cell Biology, Kyoto University, Kyoto 606-8501, Japan.
⁹ School of Computer Science, McGill University, Montreal, QC H3A 2A7, Canada.
¹⁰ Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
¹¹ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
¹² Department of Pediatrics, McGill University and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
¹³ The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
¹⁴ Pediatric Hematology-Oncology, Mayo Clinic, Rochester, MN 55905, USA.
¹⁵ Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA.
¹⁶ Department of Pediatrics, Semmelweis University, H-1094 Budapest, Hungary.
¹⁷ Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul 05505, South Korea.
¹⁸ Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 30322, South Korea.
¹⁹ Department of Pathology, The Children's Memorial Health Institute, University of Warsaw, 04-730 Warsaw, Poland.
²⁰ Department of Oncology, The Children's Memorial Health Institute, University of Warsaw, 04-730 Warsaw, Poland.
²¹ Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States of America.
²² Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, QC H3T 1C5, Canada.
²³ Department of Pediatric Neurosurgery, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, QC H3T 1C5, Canada.
²⁴ University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15213, USA; Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
²⁵ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada; McGill Genome Centre, Montreal, QC H3A 0G1, Canada.
²⁶ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
²⁷ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
²⁸ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
²⁹ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada; Lady Davis Research Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
³⁰ Quantitative Life Sciences, McGill University, Montreal, QC H3A 1B9, Canada; School of Computer Science, McGill University, Montreal, QC H3A 2A7, Canada.
³¹ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada; Department of Pediatrics, McGill University and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC H3A 3J1, Canada. Electronic address: nada.jabado@mcgill.ca.
³² The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Cancer and Hematology Center, Texas Children's Hospital, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: michael.taylor@bcm.edu.
³³ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Cancer and Hematology Center, Texas Children's Hospital, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: marco.gallo@bcm.edu.

PMID: 38986619
DOI: 10.1016/j.cell.2024.06.023

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.

Keywords: 3D genome; PFA; TULIPs; brain tumor; childhood cancer; chromatin; ependymoma; epigenomics; genomics; transcriptomics.

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Declaration of interests The authors declare no competing interests.

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TULIPs decorate the three-dimensional genome of PFA ependymoma

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TULIPs decorate the three-dimensional genome of PFA ependymoma

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