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

S. Minocherhomji, C. Hansen, H. G. Kim, Y. Mang, M. Bak, P. Guldberg, N. Papadopoulos, H. Eiberg, G. D. Doh, K. Mollgard, Jens Michael Hertz, J. E. Nielsen, H. H. Ropers, Z. Tumer, N. Tommerup, V. M. Kalscheuer, A. Silahtaroglu

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Abstrakt

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.
OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind23
Udgave nummer23
Sider (fra-til)6163-6176
ISSN0964-6906
DOI
StatusUdgivet - 2014

Bibliografisk note

ISI Document Delivery No.: AX2MF Times Cited: 0 Cited Reference Count: 65 Minocherhomji, Sheroy Hansen, Claus Kim, Hyung-Goo Mang, Yuan Bak, Mads Guldberg, Per Papadopoulos, Nickolas Eiberg, Hans Doh, Gerald Dayebga Mollgard, Kjeld Hertz, Jens Michael Nielsen, Jorgen E. Ropers, Hans-Hilger Tumer, Zeynep Tommerup, Niels Kalscheuer, Vera M. Silahtaroglu, Asli Lundbeck Foundation; Danish National Research Foundation; Danish National Research Council; Danish Ministry of Science, Technology and Innovation; National Genome Research Network (NGFN); Marie Curie RTN 'Chromatin Plasticity' (EU FP6) grant [MRTN - CT-2006-035733]; University of Copenhagen, Denmark This study was supported by the Lundbeck Foundation (A.S., N.T.), the Danish National Research Foundation (N.T.), the Danish National Research Council and the Danish Ministry of Science, Technology and Innovation, and the National Genome Research Network (NGFN). S.M. was a Marie Curie Early Stage Research Fellow funded by the Marie Curie RTN 'Chromatin Plasticity' (EU FP6) grant (MRTN - CT-2006-035733) awarded to A.S. Funding to pay the Open Access publication charges for this article was provided by the University of Copenhagen, Denmark. 0 OXFORD UNIV PRESS OXFORD HUM MOL GENET

Citationsformater

Minocherhomji, S., Hansen, C., Kim, H. G., Mang, Y., Bak, M., Guldberg, P., Papadopoulos, N., Eiberg, H., Doh, G. D., Mollgard, K., Hertz, J. M., Nielsen, J. E., Ropers, H. H., Tumer, Z., Tommerup, N., Kalscheuer, V. M., & 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