Non-coding genome functions in cancer
[eng] Historically, cancer genomics has predominantly focused on coding regions. Current knowledge suggests that non-coding mutations are likely crucial in driving the mechanisms that regulate gene activity, potentially by affecting the epigenome, however, our knowledge about the impact of non-codin...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/203864 |
| Acceso en línea: | https://hdl.handle.net/2445/203864 http://hdl.handle.net/10803/689421 |
| Access Level: | acceso abierto |
| Palabra clave: | Càncer Epigenètica Cromatina Mutació (Biologia) Genòmica Cancer Epigenetics Chromatin Mutation (Biology) Genomics |
| Sumario: | [eng] Historically, cancer genomics has predominantly focused on coding regions. Current knowledge suggests that non-coding mutations are likely crucial in driving the mechanisms that regulate gene activity, potentially by affecting the epigenome, however, our knowledge about the impact of non-coding mutations on cancer development is limited. Insulinomas are rare neuroendocrine tumors arising from the pancreatic $\beta$-cells. While retaining the ability to produce insulin, insulinomas feature aberrant proliferation and altered hormone secretion resulting in failure to maintain glucose homeostasis. To gain insights into the role of non-coding mutations in insulinoma, we integrated novel regulatory genome-wide maps derived by profiling gene expression and H3K27ac deposition with genetic WGS aberrations. We unravel a significant enrichment of somatic mutations in non-coding regulatory regions active in normal and tumoral pancreatic islets which associate with differential H3K27ac deposition and RNA expression. These regions impact insulin secretion, tumor development and epigenetic modifying genes, including critical components of the polycomb complex. Interestingly, when we considered all identified genetic alterations potentially related to tumor development, encompassing both coding and noncoding genetic alterations, we discovered an enrichment of epigenetic modifiers among the genes mutated in insulinomas. Our results suggest that aberrations in the non-coding genome play a significant role in tumor development in $\beta$-cell-derived neoplasms, indicating histone modifier pathway as a possible driven mechanism in insulinoma transformation. In the same line, chromatin contact profiling is increasingly employed in regulatory genomics to understand interactions between distant genomic elements and regulatory relationships. Growing evidence suggests that changes in chromatin interactions and structure are major contributors to the misregulation of gene transcription in various diseases, including cancer. Therefore, understanding chromatin conformation in the context of cancer is crucial for unraveling the process of tumorigenesis. However, translating observed changes in chromatin structure into an understanding of the functional regulatory aberrations that drive cancer remains a significant challenge. To address this challenge, I have been developing UMI4Cats, an R package that facilitates processing, analyzing and visualizing data obtained by UMI-4C experiments. This innovative tool has been successfully applied to investigate primary epimutations in Lynch syndrome and the transdifferentiation of B-cell leukemia, exhibiting its potential in advancing our understanding the role of chromatin remodeling in cancer. |
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