한빛사논문
- 조회1,121
Hyobin Jeong 1,18,20, Karen Grimes 1,2,20, Kerstin K. Rauwolf 3, Peter-Martin Bruch 4,5,6, Tobias Rausch 1,5, Patrick Hasenfeld 1, Eva Benito 1, Tobias Roider 1,4,5, Radhakrishnan Sabarinathan 7, David Porubsky 8,9,19, Sophie A. Herbst 4,5, Büşra Erarslan-Uysal 5,10, Johann-Christoph Jann 11, Tobias Marschall 12, Daniel Nowak 11, Jean-Pierre Bourquin 3, Andreas E. Kulozik 5,10, Sascha Dietrich 4,5,6,13, Beat Bornhauser 3, Ashley D. Sanders 1,14,15,16,21 & Jan O. Korbel 1,5,17,21
1Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
2Faculty of Biosciences, EMBL and Heidelberg University, Heidelberg, Germany.
3Division of Pediatric Oncology, University Children’s Hospital, Zürich, Switzerland.
4Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
5Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.
6Department of Hematology and Oncology, University Hospital Düsseldorf, Düsseldorf, Germany.
7National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India.
8Center for Bioinformatics, Saarland University, Saarbrücken, Germany.
9Max Planck Institute for Informatics, Saarbrücken, Germany.
10Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg and Hopp Children’s Cancer Center, Heidelberg, Germany.
11Department of Hematology and Oncology, Medical Faculty Mannheim of the Heidelberg University, Heidelberg, Germany.
12Institute for Medical Biometry and Bioinformatics, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
13Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
14Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
15Berlin Institute of Health (BIH), Berlin, Germany.
16Charité-Universitätsmedizin, Berlin, Germany.
17Bridging Research Division on Mechanisms of Genomic Variation and Data Science, German Cancer Research Center (DKFZ), Heidelberg, Germany.
18Present address: Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Republic of Korea.
19Present address: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
20These authors contributed equally: Hyobin Jeong, Karen Grimes
21These authors jointly supervised this work: Ashley D. Sanders, Jan O. Korbel
Corresponding authors : Correspondence to Ashley D. Sanders or Jan O. Korbel.
Abstract
Somatic structural variants (SVs) are widespread in cancer, but their impact on disease evolution is understudied due to a lack of methods to directly characterize their functional consequences. We present a computational method, scNOVA, which uses Strand-seq to perform haplotype-aware integration of SV discovery and molecular phenotyping in single cells by using nucleosome occupancy to infer gene expression as a readout. Application to leukemias and cell lines identifies local effects of copy-balanced rearrangements on gene deregulation, and consequences of SVs on aberrant signaling pathways in subclones. We discovered distinct SV subclones with dysregulated Wnt signaling in a chronic lymphocytic leukemia patient. We further uncovered the consequences of subclonal chromothripsis in T cell acute lymphoblastic leukemia, which revealed c-Myb activation, enrichment of a primitive cell state and informed successful targeting of the subclone in cell culture, using a Notch inhibitor. By directly linking SVs to their functional effects, scNOVA enables systematic single-cell multiomic studies of structural variation in heterogeneous cell populations.
논문정보
- Research article
- 2022년 11월 (BRIC 등록일 2023-01-16)
- 국외 연구진
- 생명과학 > 노화/암생물학
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