Tumor protein 53 (TP53) is a tumor suppressor gene that is frequently mutated in urinary bladder tumors in both humans and animals. In cattle, urinary bladder tumors have been reported as occurring spontaneously as well as in conjunction with bracken fern consumption-induced bovine enzootic hematuria (BEH). The goal of this study was to evaluate various types of bovine urinary bladder neoplasms for the presence of TP53 alterations, using the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method. DNA was extracted from both epithelial and mesenchymal urinary bladder tumor samples in cattle, associated with the chronic consumption of bracken fern. PCR was performed using primers targeted to exons 5 to 8, following electrophoresis and isolation, and the products were assessed by SSCP. Tumors in which alterations in the electrophoresis patterns were noted included hemangiomas, papillomas, and carcinomas in situ. Exemplars of these tumor types were selected for sequencing, and although no changes were noted in the 5 to 8 exon range, on either side of the designed primers for exon 6, there was some portion of intron 6 in which sequencing demonstrated a deletion of the thyamine nucleotide at position 9332. In summary, although mutations were not observed within exons 5 to 8, this represents the first report of an intronic mutation in the TP53 gene in association with bovine urinary bladder tumors. Mutations within introns can predispose tissues to the development of cancer, and therefore, a possible association between mutations of the introns of TP53 and the development of urinary bladder tumors in cattle with BEH should be further investigated.
Introduction
Post-traumatic stress disorder (PTSD), is associated with an elevated risk of neurodegenerative disorders, but the molecular mechanism was not wholly identified. Aberrant methylation status and miRNA expression pattern have been identified to be associated with PTSD, but their complex regulatory networks remain largely unexplored.
Methods
The purpose of this study was to identify the key genes/pathways related to neurodegenerative disorder development in PTSD by evaluating epigenetic regulatory signature (DNA methylation and miRNA) using an integrative bioinformatic analysis. We integrated DNA expression array data with miRNA and DNA methylation array data - obtained from the GEO database- to evaluate the epigenetic regulatory mechanisms.
Results
Our results indicated that target genes of dysregulated miRNAs were significantly related to several neurodegenerative diseases. Several dysregulated genes in the neurodegeneration pathways interacted with some members of the miR-17 and miR-15/107 families. Our analysis indicated that APP/CaN/NFATs signaling pathway was dysregulated in the peripheral blood samples of PTSD. Besides, the DNMT3a and KMT2D genes, as the encoding DNA and histone methyltransferase enzymes, were upregulated, and DNA methylation and miRNA regulators were proposed as critical molecular mechanisms. Our study found dysregulation of circadian rhythm as the CLOCK gene was upregulated and hypomethylated at TSS1500 CpGs S_shores and was also a target of several dysregulated miRNAs.
Conclusion
In conclusion, we found evidence of a negative feedback loop between stress oxidative, circadian rhythm dysregulation, miR-17 and miR-15/107 families, some essential genes involved in neuronal and brain cell health, and KMT2D/DNMT3a in the peripheral blood samples of PTSD.
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