Implications of noncoding regulatory functions in the development of insulinomas

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 t...

Full description

Bibliographic Details
Authors: Ramos-Rodríguez, Mireia, Subirana Granés, Marc, Norris, Richard, Sordi, Valeria, Fernández, Ángel, Fuentes-Páez, Georgina, Pérez-González, Beatriz, Berenguer Balaguer, Clara, Chowdhury, Murad, Corripio, Raquel, Partelli, Stefano, López Bigas, Núria, Pellegrini, Silvia, Montanya Mias, Eduard, Nacher, Montserrat, Falconi, Massimo, Layer, Ryan, Rovira, Meritxell, González Pérez, Abel, Piemonti, Lorenzo, Pasquali, Lorenzo, Raurell Vila, Helena
Format: article
Status:Published version
Publication Date:2024
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/215896
Online Access:https://hdl.handle.net/2445/215896
Access Level:Open access
Keyword:Epigènesi
Expressió gènica
Cromatina
Tumors
Epigenesis
Gene expression
Chromatin
Description
Summary: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.

Similar Items