| Date: |
2022 |
| Abstract: |
Genomic rearrangements are known to result in proto-oncogene deregulation in many cancers, but the link to 3D genome structure remains poorly understood. Here, we used the highly predictive heteromorphic polymer (HiP-HoP) model to predict chromatin conformations at the proto-oncogene CCND1 in healthy and malignant B cells. After confirming that the model gives good predictions of Hi-C data for the nonmalignant human B cell-derived cell line GM12878, we generated predictions for two cancer cell lines, U266 and Z-138. These possess genome rearrangements involving CCND1 and the immunoglobulin heavy locus (IGH), which we mapped using targeted genome sequencing. Our simulations showed that a rearrangement in U266 cells where a single IGH super-enhancer is inserted next to CCND1 leaves the local topologically associated domain (TAD) structure intact. We also observed extensive changes in enhancer-promoter interactions within the TAD, suggesting that it is the downstream chromatin remodeling which gives rise to the oncogene activation, rather than the presence of the inserted super-enhancer DNA sequence per se. Simulations of the IGH-CCND1 reciprocal translocation in Z-138 cells revealed that an oncogenic fusion TAD is created, encompassing CCND1 and the IGH super-enhancers. We predicted how the structure and expression of CCND1 changes in these different cell lines, validating this using qPCR and fluorescence in situ hybridization microscopy. Our work demonstrates the power of polymer simulations to predict differences in chromatin interactions and gene expression for different translocation breakpoints. |
| Grants: |
"la Caixa" Foundation LCF/BQ/PI19/11690001
Agencia Estatal de Investigación RTI2018-094788-A-I00
Ministerio de Economía y Competitividad 48050
|
| Note: |
Work in the D.R. laboratory is supported by a Wellcome Trust Seed Award in Science (206103/Z/17/Z). B.M.J. acknowledges funding from Federación Española de Enfermedades Raras/Ministry of Science and Innovation-Spanish State Research Agency under the project RTI2018-094788-A-I00, and La Caixa Banking Foundation under the r project LCF/BQ/PI19/11690001. Work in the L.J.R. laboratory was supported by CCLG Little Princess Trust (N.K.) and a Medical Research Council DiMeN DTP studentship (D.K.). C.A.B. acknowledges support from the European Research Council (ERC CoG 648050 THREEDCELLPHYSICS). |
| Rights: |
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: |
Anglès |
| Document: |
Article ; recerca ; Versió publicada |
| Published in: |
Genome research, Vol. 32 Núm. 8 (july 2022) , p. 1355-1366, ISSN 1549-5469 |
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