Telomere shortening and telomere position effect in mild ring 17 syndrome

Abstract

BackgroundRing chromosome 17 syndrome is a rare disease that arises from the breakage and reunion of the short and long arms of chromosome 17. Usually this abnormality results in deletion of genetic material, which explains the clinical features of the syndrome. Moreover, similar phenotypic features have been observed in cases with complete or partial loss of the telomeric repeats and conservation of the euchromatic regions. We studied two different cases of ring 17 syndrome, firstly, to clarify, by analyzing gene expression analysis using real-time qPCR, the role of the telomere absence in relationship with the clinical symptoms, and secondly, to look for a new model of the mechanism of ring chromosome transmission in a rare case of familial mosaicism, through cytomolecular and quantitative fluorescence in-situ hybridization (Q-FISH) investigations.ResultsThe results for the first case showed that the expression levels of genes selected, which were located close to the p and q ends of chromosome 17, were significantly downregulated in comparison with controls. Moreover, for the second case, we demonstrated that the telomeres were conserved, but were significantly shorter than those of age-matched controls; data from segregation analysis showed that the ring chromosome was transmitted only to the affected subjects of the family.ConclusionsSubtelomeric gene regulation is responsible for the phenotypic aspects of ring 17 syndrome; telomere shortening influences the phenotypic spectrum of this disease and strongly contributes to the familial transmission of the mosaic ring. Together, these results provide new insights into the genotype-phenotype relationships in mild ring 17 syndrome.

Distributed gene expression modelling for exploring variability in epigenetic function

“…The three mesodermal derivatives GM12878, K562 and HUVEC cluster together, suggesting that residuals are partially non-random and instead convey meaningful biological information. Consistently, it is evident that the expression levels of many genes are poorly predicted across all eight cell-lines, presumably capturing divergence from histone modification-mediated regulation (explored in detail in our previous study [2]) …”

“…Taken together, these results indicate that gene-specific residuals are non-random and indicative of genes that are inherently difficult to model from histone modification data. The existence of genes with transcriptional activity apparently decoupled from the local epigenetic landscape has been explored in detail in our previous study [2].

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“…The maximum bin-width, d ∗ , is traditionally set to 2000 to approximate the average width of ChIP-seq binding regions. Different implementations of ϕ are used for histone modifications (constrained sum-of-tags) versus transcription factors (exponentially decaying affinity) due to their dissimilar ChIP-seq binding profiles [2]: where hyperparameter d 0 controls the strength of exponential decay for quantifying transcription factor interactions and is traditionally set to d 0 =5000. The resultant matrix of gene-level epigenetic scores, , is then log (or arsinh)-transformed and quantile-normalised for use in a regression model.…”

“…Previous studies by our lab [1–3] and others [4, 5] have leveraged the statistical power of modelling genes as observations of regulatory activity (versus variables in network-based analyses [6, 7]) to gain new insight into the function and interactions of transcription factors, histone modifications and DNA methylation. Recent applications include: inference of transcription factor roles from their respective binding motifs [8]; identification of regulatory elements responsible for differential expression patterns [9]; exploring the relationship between gene expression and chromatin organisation [2]; and comparative analysis of the transcriptome across distant species [10]. …”

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

“…Other histone post-translational modifications and non-coding RNAs could be involved in transgenerational transmission of the paternal epigenetic program. At least 24 post-translational histone modifications were identified in sperm, which includes 4 unique to sperm (129), suggesting a possible role of these marks in mediating the flow of information between generations. Histone H4 acetylation, which plays important role in spermatogenesis and early zygote, is the most plausible candidate.…”