Implications of noncoding regulatory functions in the development of insulinomas.

IF 11.1 Q1 CELL BIOLOGY Cell genomics Pub Date : 2024-08-14 Epub Date: 2024-07-02 DOI:10.1016/j.xgen.2024.100604
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
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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.

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非编码调控功能对胰岛素瘤发展的影响。
胰岛素瘤是由胰腺β细胞引起的罕见神经内分泌肿瘤,其特点是异常增殖和胰岛素分泌改变,导致葡萄糖稳态失调。为了揭示非编码调控区及其畸变在这些肿瘤发生中的作用,我们将表观遗传学和转录组分析与全基因组测序结合起来。结果,我们发现了与调控功能变化相关的体细胞突变。至关重要的是,这些区域会影响胰岛素分泌、肿瘤发生和表观遗传修饰基因,包括多聚酶复合体成分。染色质重塑在患者共有的胰岛素瘤选择性区域中非常明显,这些区域包含一组以 SOX17 结合基序为主的特定调控序列。此外,这些区域中有许多在β细胞中受到H3K27me3抑制,这表明肿瘤的转变涉及多聚酶靶向结构域的去抑制。我们的研究汇编了影响β细胞功能和转归的异常顺式调控元件,这些元件会影响β细胞向胰岛素瘤的发展,我们的研究还提供了一个框架来识别编码和非编码驱动突变。
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