Implications of noncoding regulatory functions in the development of insulinomas

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• dc.contributor.author Ramos-Rodríguez, Mireia
• dc.contributor.author Subirana-Granés, Marc
• dc.contributor.author Norris, Richard
• dc.contributor.author Fernández Ruiz, Ángel
• dc.contributor.author Fuentes Páez, Georgina
• dc.contributor.author Pérez-González, Beatriz
• dc.contributor.author Berenguer Balaguer, Clara
• dc.contributor.author Raurell Vila, Helena
• dc.contributor.author López Bigas, Núria
• dc.contributor.author González-Pérez, Abel
• dc.contributor.author Pasquali, Lorenzo
• dc.date.accessioned 2024-09-17T06:23:35Z
• dc.date.available 2024-09-17T06:23:35Z
• dc.date.issued 2024
• dc.description.abstract Insulinomas are rare neuroendocrine tumors arising from pancreatic β cells, characterized by aberrant proliferation and altered insulin secretion, leading to glucose homeostasis failure. With the aim of uncovering the role of noncoding regulatory regions and their aberrations in the development of these tumors, we coupled epigenetic and transcriptome profiling with whole-genome sequencing. As a result, we unraveled somatic mutations associated with changes in regulatory functions. Critically, these regions impact insulin secretion, tumor development, and epigenetic modifying genes, including polycomb complex components. Chromatin remodeling is apparent in insulinoma-selective domains shared across patients, containing a specific set of regulatory sequences dominated by the SOX17 binding motif. Moreover, many of these regions are H3K27me3 repressed in β cells, suggesting that tumoral transition involves derepression of polycomb-targeted domains. Our work provides a compendium of aberrant cis-regulatory elements affecting the function and fate of β cells in their progression to insulinomas and a framework to identify coding and noncoding driver mutations.
• dc.description.sponsorship This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2017-86242-R and PID2020-117099RB-I00) “Unidad de Excelencia Maria de Maeztu” (CEX2018-000792-M). M.R.-R. is supported by the IMPULSO Talento Joven grant from DiabetesCERO and the EFSD/Lilly Young Investigator Award. MARBiobanc’s work was supported by grants from Instituto de Salud Carlos III/FEDER (PT20/00023) and the “Xarxa de Bancs de tumors” sponsored by Pla Director d'Oncologia de Catalunya (XBTC). The islet isolation has been funded by grants PI19/00246 and PI22/00334 to E.M. from Instituto de Salud Carlos III, cofinanced by the European Regional Development Fund (ERCF).
• dc.format.mimetype application/pdf
• dc.identifier.citation Ramos-Rodríguez M, Subirana-Granés M, Norris R, Sordi V, Fernández Á, Fuentes-Páez G, et al. Implications of noncoding regulatory functions in the development of insulinomas. Cell Genom. 2024 Aug 14;4(8):100604. DOI: 10.1016/j.xgen.2024.100604
• dc.identifier.doi http://dx.doi.org/10.1016/j.xgen.2024.100604
• dc.identifier.issn 2666-979X
• dc.identifier.uri http://hdl.handle.net/10230/61106
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Cell Genom. 2024 Aug 14;4(8):100604
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-86242-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-117099RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2018-000792-M
• dc.rights © 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword Beta cell
• dc.subject.keyword Cancer
• dc.subject.keyword Diabetes
• dc.subject.keyword Epigenetics
• dc.subject.keyword Insulinoma
• dc.subject.keyword Pancreas
• dc.subject.keyword Regulatory genomics
• dc.title Implications of noncoding regulatory functions in the development of insulinomas
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion