Abstract
Background: Ultra-conserved non-coding elements (UCNEs) are genomic sequences that exhibit > 95% sequence identity between humans, mammals, birds, reptiles, and fish. Recent findings reported their functional role in cancer. The aim of this study was to evaluate the DNA methylation modifications of UNCEs in squamous cell carcinoma (SCC) from different mammal species. Methods: Fifty SCCs from 26 humans, 17 cats, 3 dogs, 1 horse, 1 bovine, 1 badger, and 1 porcupine were investigated. Fourteen feline stomatitis and normal samples from 36 healthy human donors, 7 cats, 5 dogs, 5 horses, 2 bovines and 1 badger were collected as normal controls. Bisulfite next generation sequencing evaluated the DNA methylation level from seven UCNEs (uc.160, uc.283, uc.416, uc.339, uc.270, uc.299, and uc.328). Results: 57/59 CpGs were significantly different according to the Kruskal–Wallis test (p < 0.05) comparing normal samples with SCC. A common DNA hypermethylation pattern was observed in SCCs from all the species evaluated in this study, with an increasing trend of hypermethylation starting from normal mucosa, through stomatitis to SCC. Conclusions: Our findings indicate that UCNEs are hypermethylated in human SCC, and this behavior is also conserved among different species of mammals.
Highlights
Comparative studies on whole vertebrate genomes identified highly conserved non-coding sequences with length >200 bp, called ultra-conserved non-coding elements (UCNEs) [1,2]
We found an increasing trend of methylation from normal tissue, showing the lowest levels, through feline stomatitis, exhibiting an intermediate level, and to hypermethylated squamous cell carcinoma (SCC), especially for ac.160, uc.299, uc.328, uc.339, and uc
We think that the latter is the most reliable method to detect a clear epigenetic aberration, as we identified a variable range of methylation levels among different species both for SCCs and normal samples
Summary
Comparative studies on whole vertebrate genomes identified highly conserved non-coding sequences with length >200 bp, called ultra-conserved non-coding elements (UCNEs) [1,2]. Most UCNEs were found in clusters, and more often than expected by chance near coding regions for transcription factors and molecules involved in development These features have suggested the hypothesis that UCNEs may be candidate regulatory elements with a crucial role in early stages of vertebrate development and differentiation. They harbor important sequence features, such as binding sites of developmental transcription factors to coordinate the expression of essential genes, which is why they were readily conserved over the long course of evolution [5]. Ultra-conserved non-coding elements (UCNEs) are genomic sequences that exhibit > 95% sequence identity between humans, mammals, birds, reptiles, and fish. Recent findings reported their functional role in cancer. A common DNA hypermethylation pattern was observed in SCCs from all the species evaluated in this study, with an increasing trend of hypermethylation starting from normal mucosa, through stomatitis to SCC
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