Implications of noncoding regulatory functions in the development of insulinomas

Ramos-Rodríguez, Mireia; Subirana-Granés, Marc; Norris, Richard; Fernández Ruiz, Ángel; Fuentes Páez, Georgina; Pérez-González, Beatriz; Berenguer Balaguer, Clara; Raurell Vila, Helena; López Bigas, Núria; González-Pérez, Abel; Pasquali, Lorenzo

doi:http://dx.doi.org/10.1016/j.xgen.2024.100604

Implications of noncoding regulatory functions in the development of insulinomas

Llicència

Citació

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

Resum

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.