Mireia Ramos-Rodríguez, Marc Subirana-Granés, Richard Norris, Valeria Sordi, Ángel Fernández, Georgina Fuentes-Páez, Beatriz Pérez-González, Clara Berenguer Balaguer, Helena Raurell-Vila, Murad Chowdhury, Raquel Corripio, Stefano Partelli, Núria López-Bigas, Silvia Pellegrini, Eduard Montanya, Montserrat Nacher, Massimo Falconi, Ryan Layer, Meritxell Rovira, Abel González-Pérez, Lorenzo Piemonti, Lorenzo Pasquali
{"title":"Implications of noncoding regulatory functions in the development of insulinomas.","authors":"Mireia Ramos-Rodríguez, Marc Subirana-Granés, Richard Norris, Valeria Sordi, Ángel Fernández, Georgina Fuentes-Páez, Beatriz Pérez-González, Clara Berenguer Balaguer, Helena Raurell-Vila, Murad Chowdhury, Raquel Corripio, Stefano Partelli, Núria López-Bigas, Silvia Pellegrini, Eduard Montanya, Montserrat Nacher, Massimo Falconi, Ryan Layer, Meritxell Rovira, Abel González-Pérez, Lorenzo Piemonti, Lorenzo Pasquali","doi":"10.1016/j.xgen.2024.100604","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1000,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11406191/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell genomics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.xgen.2024.100604","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/2 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.