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Background  Fragile X syndrome (FXS) is the most common form of inherited intellectual disability, resulting from the loss of function of the  fragile X mental retardation 1  ( FMR1 ) gene. The molecular pathways associated with  FMR1  epigenetic silencing are still elusive, and their characterization may enhance the discovery of novel therapeutic targets as well as the development of novel clinical biomarkers for disease status.    Results  We have deployed customized epigenomic profiling assays to comprehensively map the  FMR1  locus chromatin landscape in peripheral mononuclear blood cells (PBMCs) from eight FXS patients and in fibroblast cell lines derived from three FXS patient. Deoxyribonucleic acid (DNA) methylation (5-methylcytosine (5mC)) and hydroxymethylation (5-hydroxymethylcytosine (5hmC)) profiling using methylated DNA immunoprecipitation (MeDIP) combined with a custom  FMR1  microarray identifies novel regions of DNA (hydroxy)methylation changes within the  FMR1  gene body as well as in proximal flanking regions. At the region surrounding the  FMR1  transcriptional start sites, increased levels of 5mC were associated to reciprocal changes in 5hmC, representing a novel molecular feature of FXS disease. Locus-specific validation of  FMR1  5mC and 5hmC changes highlighted inter-individual differences that may account for the expected DNA methylation mosaicism observed at the  FMR1  locus in FXS patients. Chromatin immunoprecipitation (ChIP) profiling of  FMR1  histone modifications, together with 5mC/5hmC and gene expression analyses, support a functional relationship between 5hmC levels and  FMR1  transcriptional activation and reveal cell-type specific differences in  FMR1  epigenetic regulation. Furthermore, whilst 5mC  FMR1  levels positively correlated with FXS disease severity (clinical scores of aberrant behavior), our data reveal for the first time an inverse correlation between 5hmC  FMR1  levels and FXS disease severity.    Conclusions  We identify novel, cell-type specific, regions of  FMR1  epigenetic changes in FXS patient cells, providing new insights into the molecular mechanisms of FXS. We propose that the combined measurement of 5mC and 5hmC at selected regions of the  FMR1  locus may significantly enhance FXS clinical diagnostics and patient stratification.    Electronic supplementary material  The online version of this article (doi:10.1186/s13148-016-0181-x) contains supplementary material, which is available to authorized users.

clinical epigenetics

Reciprocal changes in DNA methylation and hydroxymethylation and a broad repressive epigenetic switch characterize FMR1 transcriptional silencing in fragile X syndrome