RESUMO
MOTIVATION: UMI-4C, a technique that combines chromosome conformation capture (4C) and unique molecular identifiers (UMI), is widely used to profile and quantitatively compare targeted chromosomal contact profiles. The analysis of UMI-4C experiments presents several computational challenges, including the removal of the PCR duplication bias and the identification of differential chromatin contacts. RESULTS: We have developed UMI4Cats (UMI-4C Analysis Turned Simple), an R package that facilitates processing, analyzing and visualizing of data obtained by UMI-4C experiments. AVAILABILITY AND IMPLEMENTATION: UMI4Cats is implemented as an R package supported on Linux, MacOS and MS Windows. UMI4Cats is available from Bioconductor (https://www.bioconductor.org/packages/release/bioc/html/UMI4Cats.html) and GitHub (https://github.com/Pasquali-lab/UMI4Cats). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Cromatina , Software , CromossomosRESUMO
Insulinomas are rare neuroendocrine tumors arising from pancreatic ß 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 ß 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 ß cells in their progression to insulinomas and a framework to identify coding and noncoding driver mutations.
Assuntos
Insulinoma , Humanos , Insulinoma/genética , Insulinoma/patologia , Insulinoma/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Mutação , Regulação Neoplásica da Expressão Gênica , Epigênese Genética , Montagem e Desmontagem da Cromatina/genéticaRESUMO
The early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic ß cells. Here we show that exposure to proinflammatory cytokines reveals a marked plasticity of the ß-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the ß-cell transcriptome, proteome and three-dimensional chromatin structure. Our data indicate that the ß-cell response to cytokines is mediated by the induction of new regulatory regions as well as the activation of primed regulatory elements prebound by islet-specific transcription factors. We find that T1D-associated loci are enriched with newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human ß cells. Our study illustrates how ß cells respond to a proinflammatory environment and implicate a role for stimulus response islet enhancers in T1D.