Beta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. The molecular mechanisms through which beta cell hierarchy is established remain poorly understood. The neuronatin (Nnat) gene is imprinted in mice and humans and is required for normal insulin synthesis and secretion. Here, we demonstrate that Nnat is differentially expressed in a discrete beta cell population in a developmental-stage and DNA methylation (DNMT3A)-dependent manner. Explored in mice expressing eGFP from a bacterial artificial chromosome-expressed transgene, NNAT+cells displayed a discrete transcriptome, and appear to represent a beta cell population specialised for insulin production. Correspondingly, highly connected hub cells were less abundant in the NNAT+population. These findings demonstrate that differential DNA methylation at Nnat represents a novel means through which beta cell heterogeneity is established.
The implementation of early-detection technologies and prognostic biomarkers are imperative, specifically in cities highly exposed to environmental carcinogens, such as PAHs and Arsenic. This study proposed to evaluate cfDNA levels and determine CNAs in serum cfDNA in LC and PNL patients. The study enrolled a total of 107 people, from the Metropolitan (N=51) and Antofagasta (N=56) regions, with medium or high LC risk. The cfDNA was isolated from serum aliquots using Qiagen QIAamp DNA mini kit. HMMs analysis in cfDNA, was used as a probabilistic model to determine an unknown sequence and defined Minimal Common Regions (MCRs) of recurring DNA gains and losses. This study shows that cfDNA levels increased during malignancy of LC but not significantly during premalignant lesions or pre-invasive stages. The cfDNA could be used as a complementary tool to prognosis and evolution of LC, with high precision (specificity of 87.3% and PNV of 76.4%). Additionally, the cfDNA carry some chromosomal aberrations related with the lung tumorigenesis process that could be used to confirm a suspected case of LC. Within these alterations our results suggest the loss of specific chromosomic fragments, contain genes related with inflammation response (SERPING1), humoral immune response (IGCK), innate immunity and epithelial integrity (CTNN1), tumor suppressor (MAP2K4, DMTF1 and ABCB4), and response to oxidative stress (COX10). In conclusion, these biomarkers in cfDNA, could have a great potential as screening methods in population with high risk for LC.
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