title: C9orf72 is differentially expressed in the central nervous system and myeloid cells and consistently reduced in C9orf72, MAPT and GRN mutation carriers.
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.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller Strasse 23, Tübingen, 72076, Germany. patrizia.rizzu@dzne.de.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rizzu
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller Strasse 23, Tübingen, 72076, Germany.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Blauwendraat
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller Strasse 23, Tübingen, 72076, Germany.
authors.forename: Sasja
authors.initials: S
authors.lastname: Heetveld
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller Strasse 23, Tübingen, 72076, Germany.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Lynes
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller Strasse 23, Tübingen, 72076, Germany.
authors.forename: Melissa
authors.initials: M
authors.lastname: Castillo-Lizardo
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller Strasse 23, Tübingen, 72076, Germany.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Dhingra
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller Strasse 23, Tübingen, 72076, Germany.
authors.forename: Elwira
authors.initials: E
authors.lastname: Pyz
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller Strasse 23, Tübingen, 72076, Germany.|Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hobert
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller Strasse 23, Tübingen, 72076, Germany.|Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller Strasse 23, Tübingen, 72076, Germany.|Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
authors.forename: Javier
authors.initials: J
authors.lastname: Simón-Sánchez
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller Strasse 23, Tübingen, 72076, Germany.
authors.forename: Margherita
authors.initials: M
authors.lastname: Francescatto
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Otfried-Müller Strasse 23, Tübingen, 72076, Germany.|Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D000073885:C9orf72 Protein; D002490:Central Nervous System / Q000378:metabolism*; D016208:Databases, Factual / Q000592:standards / Q000706:statistics & numerical data; D057180:Frontotemporal Dementia / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D022423:Myeloid Cells / Q000378:metabolism*; D000077153:Progranulins; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors; C054369:MAPT protein, human; D000077153:Progranulins; D011506:Proteins; D016875:tau Proteins
keywords: C9orf72 risk haplotype; Frontotemporal dementia; Hexanucleotide repeat expansion; Neurodegeneration