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Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia.

Minocherhomji S, Hansen C, Kim HG, Mang Y, Bak M, Guldberg P, Papadopoulos N, Eiberg H, Doh GD, Møllgård K, Hertz JM, Nielsen JE, Ropers HH, Tümer Z, Tommerup N, Kalscheuer VM, Silahtaroglu A - Hum. Mol. Genet. (2014)

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.

View Article: PubMed Central - PubMed

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.

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Monoallelic changes in DNA methylation at DLGAP4 are induced by the t(8;20) translocation. (A and B) Normalized unique MBD-Seq peak reads in carriers (III.2, III.7) and four normal unrelated controls (Controls 1–4) showing genome-wide distribution of reads and peaks. (C and D) UCSC genome browser views showing the translocated DLGAP4 CpG island (CpG 107) to be differentially methylated (hypermethylated: MBD-Seq and hypomethylated: MRE-Seq) in carriers and completely hypomethylated in controls. Rectangles show regions used for bisulfite allelic sequencing (see below). (E) Bisulfite allelic sequencing showing the disrupted DLGAP4 CpG island (CpG 107) to be hypermethylated (individual CpGs: filled circles) in the somatic cells of all male and female carriers tested. CpG methylation at DLGAP4 is absent in purified spermatozoa DNA from translocation carrier IV.9 but is re-established in his somatic cells. (F) The undisrupted DLGAP4 CpG island (CpG 107) is hypomethylated (individual CpGs: hollow circles) in all carriers. DLGAP4 CpG island is bi-allelically hypomethylated in all related (IV.6 and V.6) and unrelated phenotypically normal controls (Controls 1 and 2).
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DDU337F2: Monoallelic changes in DNA methylation at DLGAP4 are induced by the t(8;20) translocation. (A and B) Normalized unique MBD-Seq peak reads in carriers (III.2, III.7) and four normal unrelated controls (Controls 1–4) showing genome-wide distribution of reads and peaks. (C and D) UCSC genome browser views showing the translocated DLGAP4 CpG island (CpG 107) to be differentially methylated (hypermethylated: MBD-Seq and hypomethylated: MRE-Seq) in carriers and completely hypomethylated in controls. Rectangles show regions used for bisulfite allelic sequencing (see below). (E) Bisulfite allelic sequencing showing the disrupted DLGAP4 CpG island (CpG 107) to be hypermethylated (individual CpGs: filled circles) in the somatic cells of all male and female carriers tested. CpG methylation at DLGAP4 is absent in purified spermatozoa DNA from translocation carrier IV.9 but is re-established in his somatic cells. (F) The undisrupted DLGAP4 CpG island (CpG 107) is hypomethylated (individual CpGs: hollow circles) in all carriers. DLGAP4 CpG island is bi-allelically hypomethylated in all related (IV.6 and V.6) and unrelated phenotypically normal controls (Controls 1 and 2).

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.


Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia.

Minocherhomji S, Hansen C, Kim HG, Mang Y, Bak M, Guldberg P, Papadopoulos N, Eiberg H, Doh GD, Møllgård K, Hertz JM, Nielsen JE, Ropers HH, Tümer Z, Tommerup N, Kalscheuer VM, Silahtaroglu A - Hum. Mol. Genet. (2014)

Monoallelic changes in DNA methylation at DLGAP4 are induced by the t(8;20) translocation. (A and B) Normalized unique MBD-Seq peak reads in carriers (III.2, III.7) and four normal unrelated controls (Controls 1–4) showing genome-wide distribution of reads and peaks. (C and D) UCSC genome browser views showing the translocated DLGAP4 CpG island (CpG 107) to be differentially methylated (hypermethylated: MBD-Seq and hypomethylated: MRE-Seq) in carriers and completely hypomethylated in controls. Rectangles show regions used for bisulfite allelic sequencing (see below). (E) Bisulfite allelic sequencing showing the disrupted DLGAP4 CpG island (CpG 107) to be hypermethylated (individual CpGs: filled circles) in the somatic cells of all male and female carriers tested. CpG methylation at DLGAP4 is absent in purified spermatozoa DNA from translocation carrier IV.9 but is re-established in his somatic cells. (F) The undisrupted DLGAP4 CpG island (CpG 107) is hypomethylated (individual CpGs: hollow circles) in all carriers. DLGAP4 CpG island is bi-allelically hypomethylated in all related (IV.6 and V.6) and unrelated phenotypically normal controls (Controls 1 and 2).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222360&req=5

DDU337F2: Monoallelic changes in DNA methylation at DLGAP4 are induced by the t(8;20) translocation. (A and B) Normalized unique MBD-Seq peak reads in carriers (III.2, III.7) and four normal unrelated controls (Controls 1–4) showing genome-wide distribution of reads and peaks. (C and D) UCSC genome browser views showing the translocated DLGAP4 CpG island (CpG 107) to be differentially methylated (hypermethylated: MBD-Seq and hypomethylated: MRE-Seq) in carriers and completely hypomethylated in controls. Rectangles show regions used for bisulfite allelic sequencing (see below). (E) Bisulfite allelic sequencing showing the disrupted DLGAP4 CpG island (CpG 107) to be hypermethylated (individual CpGs: filled circles) in the somatic cells of all male and female carriers tested. CpG methylation at DLGAP4 is absent in purified spermatozoa DNA from translocation carrier IV.9 but is re-established in his somatic cells. (F) The undisrupted DLGAP4 CpG island (CpG 107) is hypomethylated (individual CpGs: hollow circles) in all carriers. DLGAP4 CpG island is bi-allelically hypomethylated in all related (IV.6 and V.6) and unrelated phenotypically normal controls (Controls 1 and 2).
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.

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.

View Article: PubMed Central - PubMed

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
Related in: MedlinePlus