| Title: |
Functional analysis of structural variants in single cells using Strand-seq |
| Authors: |
Jeong, H.; Grimes, K.; Rauwolf, K.K.; Bruch, P.M.; Rausch, T.; Hasenfeld, P.; Benito, E.; Roider, T.; Sabarinathan, R.; Porubsky, D.; Herbst, S.A.; Erarslan-Uysal, B.; Jann, J.C.; Marschall, T.; Nowak, D.; Bourquin, J.P.; Kulozik, A.E.; Dietrich, S.; Bornhauser, B.; Sanders, A.D.; Korbel, J.O. |
| Publisher Information: |
Nature Publishing Group |
| Publication Year: |
2023 |
| Collection: |
Max-Delbrueck-Center for Molecular Medicine, Berlin: MDC Repository |
| Subject Terms: |
Cancer Research; Topic 1: Genes; Cells and Cell-Based Medicine |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf; other |
| Language: |
English |
| Relation: |
https://edoc.mdc-berlin.de/id/eprint/22922/1/22922oa.pdf; https://edoc.mdc-berlin.de/id/eprint/22922/2/22922suppl.zip; Functional analysis of structural variants in single cells using Strand-seq. Jeong, H., Grimes, K., Rauwolf, K.K., Bruch, P.M., Rausch, T., Hasenfeld, P., Benito, E., Roider, T., Sabarinathan, R., Porubsky, D., Herbst, S.A., Erarslan-Uysal, B., Jann, J.C., Marschall, T., Nowak, D., Bourquin, J.P., Kulozik, A.E., Dietrich, S., Bornhauser, B., Sanders, A.D. and Korbel, J.O. Nature Biotechnology 41 (6): 832-844. June 2023; PMID:36424487; https://doi.org/10.1038/s41587-022-01551-4 |
| DOI: |
10.1038/s41587-022-01551-4 |
| Availability: |
https://edoc.mdc-berlin.de/id/eprint/22922/; https://edoc.mdc-berlin.de/22922/; https://doi.org/10.1038/s41587-022-01551-4 |
| Rights: |
cc_by_4 |
| Accession Number: |
edsbas.670113AC |
| Database: |
BASE |