Abstract
A non-coding hexanucleotide repeat expansion (HRE) in C9orf72 is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) acting through a loss of function mechanism due to haploinsufficiency of C9orf72 or a gain of function mediated by aggregates of bidirectionally transcribed HRE-RNAs translated into di-peptide repeat (DPR) proteins. To fully understand regulation of C9orf72 expression we surveyed the C9orf72 locus using Cap Analysis of Gene Expression sequence data (CAGEseq). We observed C9orf72 was generally lowly expressed with the exception of a subset of myeloid cells, particularly CD14+ monocytes that showed up to seven fold higher expression as compared to central nervous system (CNS) and other tissues. The expression profile at the C9orf72 locus showed a complex architecture with differential expression of the transcription start sites (TSSs) for the annotated C9orf72 transcripts between myeloid and CNS tissues suggesting cell and/or tissue specific functions. We further detected novel TSSs in both the sense and antisense strand at the C9orf72 locus and confirmed their existence in brain tissues and CD14+ monocytes. Interestingly, our experiments showed a consistent decrease of C9orf72 coding transcripts not only in brain tissue and monocytes from C9orf72-HRE patients, but also in brains from MAPT and GRN mutation carriers together with an increase in antisense transcripts suggesting these could play a role in regulation of C9orf72. We found that the non-HRE related expression changes cannot be explained by promoter methylation but by the presence of the C9orf72-HRE risk haplotype and unknown functional interactions between C9orf72, MAPT and GRN.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0306-7) contains supplementary material, which is available to authorized users.
Highlights
In 2011 two independent studies identified a noncoding hexanucleotide repeat expansion (HRE) in the C9orf72 gene as the major cause for chromosome 9-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with or without concomitant motor neuron disease [1, 2]
Dataset 1: Cap Analysis of Gene Expression sequence data (CAGEseq) data published in the context of the FANTOM5 promoterome project [28], which generated a comprehensive map of transcription start sites (TSSs) and their usage across 975 human and 399 mouse samples
The C9orf72 locus shows a complex transcriptional architecture in the central nervous system (CNS) and in CD14+ monocytes To characterize the transcriptional events occurring at the C9orf72 locus and identify possible new transcripts a b on the sense and antisense strands that contribute to C9orf72 expression, we used publically available CAGEseq expression data generated in the context of the FANTOM5 project [28] to investigate in which tissues and cells C9orf72 is expressed
Summary
In 2011 two independent studies identified a noncoding HRE in the C9orf gene as the major cause for chromosome 9-linked ALS and FTD with or without concomitant motor neuron disease [1, 2]. Transcribed HRE containing RNAs accumulate into RNA foci, occurring mainly in the nuclei of neurons in brain tissue and cultured cells of patients [1, 5, 6]. The C9orf DPR proteins accumulate into cytoplasmic and intranuclear inclusions in brains of patients [12,13,14,15,16]. Studies in cell culture and animal models strongly corroborate that overexpression of DPR proteins is toxic and can induce nuclear inclusions and nucleolar stress [17, 18]
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