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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 material  The online version of this article (doi:10.1186/s40478-016-0306-7) contains supplementary material, which is available to authorized users.

acta neuropathologica communications

C9orf72 is differentially expressed in the central nervous system and myeloid cells and consistently reduced in C9orf72, MAPT and GRN mutation carriers