Transcriptome-wide analysis of Agc1 downregulation in mouse oligodendrocyte precursor cells
Aspartate-glutamate carrier isoform 1 (Agc1) is a mitochondrial carrier part of the malate-aspartate shuttle, responsible for the export of aspartate and N-acetyl-aspartate from the mitochondria to the brain. Agc1 deficiency can cause an ultra-rare genetic disease reported as epileptic encephalopathy with global cerebral demyelination often caused by mutation in Slc25a12, the gene from which Agc1 is encoded. Symptoms of the disease include diffused hypomyelination, arrested psychomotor development, severe hypotonia, seizures and are common to other neurological and developmental disorders.  Oligodendrocytes are glial cells responsible for myelination and remyelination and a disruption of acetyl fluxes can severely hamper their ability to form myelin leading to abnormal neuronal functionality. In this work, we explore the transcriptome of mouse oligodendrocyte precursor cells that have been silenced for Agc1 expression, reporting results of both canonical analyses such as differential expression and pathway enrichment analyses which highlight a disruption in fatty acids synthesis from both a regulatory and enzymatic stand. We further explore the transcriptome space with a network and an alternative splicing analysis: these results taken together highlight a severe alteration at the transcriptome level, which brought us to question a possible involvement of Agc1 in transcription regulation. Overall design: In order to investigate the role of Agc1 (Slc25a12) in oligodendrocyte precursor cells, we established an Oli-Neu cell line in which AGc1 has been knocked down using shRNA. We then performed differential gene expression analysis using data obtained from 3 different replicates per condition (total of 3 wild-type samples and 3 Agc1+/-)