Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia.
Bottom Line: However, the coordinated epigenetic effects of constitutional chromosomal rearrangements that disrupt genes associated with congenital neurodevelopmental diseases are poorly understood.Disruption of DLGAP4 results in monoallelic hypermethylation of the truncated DLGAP4 promoter CpG island.Our results provide new mechanistic insight into the way a balanced chromosomal rearrangement associated with a neurodevelopmental disorder perturbs allele-specific epigenetic mechanisms at breakpoints leading to the deregulation of the truncated locus.
Affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark.Show MeSH
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Mentions: We investigated whether this rearrangement that truncated a CpG island might have induced an effect on DNA methylation (5-methylcytosine: 5-mC) or DNA hydroxymethylation (5-hydroxymethylcytosine: 5-hmC). Initially, we measured genome-wide DNA hypermethylation and hypomethylation by high-throughput MBD-Seq and MRE-Seq in genomic DNA from peripheral blood lymphocytes (PBLs; somatic cells) of two translocation carrier sisters, III.2 and III.7, and four phenotypically normal, unrelated male and female controls (Controls 1–4). We found no significant changes in DNA methylation patterns; neither on a genome-wide level (Fig. 2A and B) nor on either of the disrupted chromosomes (Supplementary Material, Fig. S1A and B), when compared with control genomes tested here and in all other control human tissues tested elsewhere (17). In strong contrast however, the disrupted DLGAP4 CpG island was differentially methylated in the two tested translocation carriers (Fig. 2C and D). All controls tested here (Fig. 2C and D) and published elsewhere remained completely hypomethylated at the same locus (17).Figure 2.
Affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark.