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

Sheroy Minocherhomji, Claus Hansen, Hyung Goo Kim, Yuan Mang, Mads Bak, Per Guldberg, Nickolas Papadopoulos, Hans Eiberg, Gerald Dayebga Doh, Kjeld Møllgård, Jens Michael Hertz, Jørgen E. Nielsen, Hans Hilger Ropers, Zeynep Tümer, Niels Tommerup, Vera M. Kalscheuer, Asli Silahtaroglu

Research output: Contribution to journalArticle

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Abstract

Genome instability, epigenetic remodelling and structural chromosomal rearrangements are hallmarks of cancer. However, the coordinated epigenetic effects of constitutional chromosomal rearrangements that disrupt genes associated with congenital neurodevelopmental diseases are poorly understood. To understand the genetic-epigenetic interplay at breakpoints of chromosomal translocations disrupting CG-rich loci, we quantified epigenetic modifications at DLGAP4 (SAPAP4), a key post-synaptic density 95 (PSD95) associated gene, truncated by the chromosome translocation t(8;20)(p12;q11.23), co-segregating with cerebellar ataxia in a five-generation family.We report significant epigenetic remodelling of the DLGAP4 locus triggered by the t(8;20)(p12;q11.23) translocation and leading to dysregulation of DLGAP4 expression in affected carriers. Disruption of DLGAP4 results in monoallelic hypermethylation of the truncated DLGAP4 promoter CpG island. This induced hypermethylation is maintained in somatic cells of carriers across several generations in a t(8;20) dependent-manner however, is erased in the germ cells of the translocation carriers. Subsequently, chromatin remodelling of the locus-perturbed monoallelic expression of DLGAP4 mRNAs and non-coding RNAs in haploid cells having the translocation. 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.

Original languageEnglish (US)
Pages (from-to)6163-6176
Number of pages14
JournalHuman Molecular Genetics
Volume23
Issue number23
DOIs
StatePublished - Dec 1 2014

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Spinocerebellar Degenerations
Epigenomics
Post-Synaptic Density
Cerebellar Ataxia
Untranslated RNA
Genetic Translocation
CpG Islands
Chromatin Assembly and Disassembly
Gene Rearrangement
Genomic Instability
Haploidy
Germ Cells
Chromosomes
Alleles
Messenger RNA
Genes
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Minocherhomji, S., Hansen, C., Kim, H. G., Mang, Y., Bak, M., Guldberg, P., ... Silahtaroglu, A. (2014). Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia. Human Molecular Genetics, 23(23), 6163-6176. https://doi.org/10.1093/hmg/ddu337

Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia. / Minocherhomji, Sheroy; Hansen, Claus; Kim, Hyung Goo; Mang, Yuan; Bak, Mads; Guldberg, Per; Papadopoulos, Nickolas; Eiberg, Hans; Doh, Gerald Dayebga; Møllgård, Kjeld; Hertz, Jens Michael; Nielsen, Jørgen E.; Ropers, Hans Hilger; Tümer, Zeynep; Tommerup, Niels; Kalscheuer, Vera M.; Silahtaroglu, Asli.

In: Human Molecular Genetics, Vol. 23, No. 23, 01.12.2014, p. 6163-6176.

Research output: Contribution to journalArticle

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 2014, 'Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia', Human Molecular Genetics, vol. 23, no. 23, pp. 6163-6176. https://doi.org/10.1093/hmg/ddu337
Minocherhomji, Sheroy ; Hansen, Claus ; Kim, Hyung Goo ; Mang, Yuan ; Bak, Mads ; Guldberg, Per ; Papadopoulos, Nickolas ; Eiberg, Hans ; Doh, Gerald Dayebga ; Møllgård, Kjeld ; Hertz, Jens Michael ; Nielsen, Jørgen E. ; Ropers, Hans Hilger ; Tümer, Zeynep ; Tommerup, Niels ; Kalscheuer, Vera M. ; Silahtaroglu, Asli. / Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 23. pp. 6163-6176.
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AU - Nielsen, Jørgen E.

AU - Ropers, Hans Hilger

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