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Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells.

ABSTRACT: Autism spectrum disorders (ASD) are complex neurodevelopmental disorders with a very large number of risk loci detected in the genome. However, at best, each of them explains rare cases, the majority being idiopathic. Genomic data on ASD derive mostly from post-mortem brain analyses or cell lines derived from blood or patient-specific induced pluripotent stem cells (iPSCS). Therefore, the transcriptional and regulatory architecture of the nervous system, particularly during early developmental periods, remains highly incomplete. To access the critical disturbances that may have occurred during pregnancy or early childhood, we recently isolated stem cells from the nasal cavity of anesthetized patients diagnosed for ASD and compared them to stem cells from gender-matched control individuals without neuropsychiatric disorders. This allowed us to discover MOCOS, a non-mutated molybdenum cofactor sulfurase-coding gene that was under-expressed in the stem cells of most ASD patients of our cohort, disturbing redox homeostasis and synaptogenesis. We now report that a divergent transcription upstream of MOCOS generates an antisense long noncoding RNA, to which we coined the name COSMOC. Surprisingly, COSMOC is strongly under-expressed in all ASD patients of our cohort with the exception of a patient affected by Asperger syndrome. Knockdown studies indicate that loss of COSMOC reduces MOCOS expression, destabilizes lipid and energy metabolisms of stem cells, but also affects neuronal maturation and splicing of synaptic genes. Impaired expression of the COSMOC/MOCOS bidirectional unit might shed new lights on the origins of ASD that could be of importance for future translational studies.

SUBMITTER: Rontani P

PROVIDER: S-EPMC8159765 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The degree of histologic cellular differentiation of a cancer has been associated with prognosis but is subjectively assessed. We hypothesized that information about tumor differentiation of individual cancers could be derived objectively from cancer gene expression data, and would allow creation of a cancer phylogenetic framework that would correlate with clinical, histologic and molecular characteristics of the cancers, as well as predict prognosis. Here we utilized mRNA expression data from 4,413 patient samples with 7 diverse cancer histologies to explore the utility of ordering samples by their distance in gene expression from that of stem cells. A differentiation baseline was obtained by including expression data of human embryonic stem cells (hESC) and human mesenchymal stem cells (hMSC) for solid tumors, and of hESC and CD34+ cells for liquid tumors. We found that the correlation distance (the degree of similarity) between the gene expression profile of a tumor sample and that of stem cells orients cancers in a clinically coherent fashion. For all histologies analyzed (including carcinomas, sarcomas, and hematologic malignancies), patients with cancers with gene expression patterns most similar to that of stem cells had poorer overall survival. We also found that the genes in all undifferentiated cancers of diverse histologies that were most differentially expressed were associated with up-regulation of specific oncogenes and down-regulation of specific tumor suppressor genes. Thus, a stem cell-oriented phylogeny of cancers allows for the derivation of a novel cancer gene expression signature found in all undifferentiated forms of diverse cancer histologies, that is competitive in predicting overall survival in cancer patients compared to previously published prediction models, and is coherent in that gene expression was associated with up-regulation of specific oncogenes and down-regulation of specific tumor suppressor genes associated with regulation of the multicellular state.

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Impaired expression of the COSMOC/MOCOS gene unit in ASD patient stem cells.

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