title: Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia.
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.
authors.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.
authors.forename: Sheroy
authors.initials: S
authors.lastname: Minocherhomji
authors.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.
authors.forename: Claus
authors.initials: C
authors.lastname: Hansen
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
authors.forename: Hyung-Goo
authors.initials: HG
authors.lastname: Kim
authors.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.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mang
authors.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.
authors.forename: Mads
authors.initials: M
authors.lastname: Bak
authors.affiliation: Danish Cancer Society, Institute of Cancer Biology, Copenhagen DK-2100, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Guldberg
authors.affiliation: Ludwig Center for Cancer Genetics, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Eiberg
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark.
authors.forename: Gerald Dayebga
authors.initials: GD
authors.lastname: Doh
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark.
authors.forename: Kjeld
authors.initials: K
authors.lastname: Møllgård
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense C DK-5000, Denmark.
authors.forename: Jens Michael
authors.initials: JM
authors.lastname: Hertz
authors.affiliation: Section for Neurogenetics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen N 2200, Denmark, Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen Ø 2100, Denmark and.
authors.forename: Jørgen E
authors.initials: JE
authors.lastname: Nielsen
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup DK-2600, Denmark.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tümer
authors.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.
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin 14195, Germany.
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.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, asli@sund.ku.dk.
authors.forename: Asli
authors.initials: A
authors.lastname: Silahtaroglu
mesh_terms: D002524:Cerebellar Ataxia / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism; D000074407:SAP90-PSD95 Associated Proteins; D014178:Translocation, Genetic
chemical_list: C000614188:DLGAP4 protein, human; D006657:Histones; D009419:Nerve Tissue Proteins; D062085:RNA, Long Noncoding; D000074407:SAP90-PSD95 Associated Proteins; C077020:histone H2A.F-Z