Epigenetic remodeling and deregulation of SAPAP4/DLGAP4 is linked with early-onset cerebellar ataxia

ABSTRACT: Epigenetic effects at the breakpoints of disease-associated balanced chromosomal rearrangements are not fully understood. To elucidate and characterize epigenetic effects of such a rearrangement, we studied the familial translocation t(8:20)(p12;q11.23) inherited across five generations together with early-onset non-progressive cerebellar ataxia. This translocation disrupts DLGAP4 and a DLGAP4 CpG island at 20q11.23, a locus encoding a brain-specific DLGAP4 mRNA (isoform a) and a gene-desert at 8p12. We find describe translocation-dependent, monoallelic epigenetic changes at DLGAP4 affecting its expression in cis. We found hypermethylation of the disrupted DLGAP4 CpG island and a delay in replication timing of this locus in multiple carriers. Hypermethylation of CpGs at the disrupted DLGAP4 CpG island is re-established in the somatic cells of each translocation carrier after being erased in their germ cells. Brain-specificity of DLGAP4 mRNA isoform a is maintained in carriers. However, this rearrangement leads to increased mono-allelic expression of another DLGAP4 mRNA isoform b from the truncated DLGAP4 locus. Furthermore, there is a translocation dependent enrichment of the conserved histone variant H2A.Z at the undisrupted DLGAP4 CpG island. Functional analyses reveal a novel intronic non-coding RNA, transcribed from the DLGAP4 promoter region and the DLGAP4 mRNA isoform a, both of which are and disrupted by the translocation, to be and highly expreed in the human brain. Using in situ hybridization we found this ncRNA to be bi-directionally expressed in human and mouse cerebellum, relative to elevated expression of DLGAP4 mRNA isoform a only in Purkinje neurons. These data provide a basis for the understanding of the roles epigenetic regulatory mechanisms transmitted through germ cells have in controlling expression of disrupted gene loci highly expressed in the human brain.

ORGANISM(S): Homo sapiens

PROVIDER: GSE31204 | GEO | 2014/07/01

SECONDARY ACCESSION(S): PRJNA145987

REPOSITORIES: GEO