Gene co-expression analysis unravels a link between C9orf72 and RNA metabolism in myeloid cells.

摘要: GGGGCC hexanucleotide repeat expansion in the promoter or intronic regions of C9orf72 is responsible for most common familial forms amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) [4]. Gain-of-function C9orf72, at mRNA and/or protein level, currently considered as a major mechanism neurodegeneration these patients [2, 5, 7]. To further elucidate genomic impact gain-of-function, we performed gene co-expression analysis using open source bioinformatics tool Multi Experiment Matrix (MEM) [1] that covers large set human transcriptomic data (n = 1794) on same expression array platform (Affymetrix HG-U133_Plus_2). This approach allowed us to identify 100 species are overall positively correlated with levels and, conversely, inversely levels. We then used “EnrichR” [3] assess two lists regard their enrichment subsets genes sharing Gene Ontology (GO) annotations i.e. belonging functional family. While did not find any significant list whose were was highly significantly enriched annotated RNA metabolism-related GO terms. These included notably terms “ncRNA metabolism” (adjusted p-value = 6.57E-6), “tRNA aminoacylation” p-value = 6.57E-6) metabolic process” (1.90E-5). Table 1 shows full which an adjusted p-value < 0.001 found. increase associates concomitant downregulation exert key functions metabolism. Altered metabolism pathological feature only mutation carriers but also bearing mutations FUS TDP43 well sporadic ALS [8]. Our observation suggests increased non-mutated may similarly trigger alterations. However, relevance such finding context remains be determined. Table 1 Enrichment levels Interestingly, among 1794 microarray studies from inverse correlations calculated, sets analyzing profile myeloid cells, particular acute leukemia by far informative giving rise correlations. In addition, it worth noting BioGPS Affymetrix atlas [9], probes reported detect much higher monocytes than neurons astrocytes. Monocytes belong lineage share many phenotypic properties microglia, although both cell types derive distinct progenitors [6]. Therefore, one consider link between could occur microglia. deserves investigation. Finally, our possibly regulator cells.