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Abstract

Different cell types have different post-mitotic maintenance requirements. Nerve cells, however, are unique in this respect as they need to survive and preserve their functional complexity for the entire lifetime of the organism and failure at any level of their supporting mechanisms, leads to a wide range of neurodegenerative conditions. Whether these differences across tissues arise from the activation of distinct cell type-specific maintenance mechanisms or the differential activation of a common molecular repertoire is not known. In order to identify the transcriptional signature of post-mitotic cellular longevity (PMCL), we compared whole genome transcriptome data from human tissues ranging in longevity from 120 days to over 70 years and found a set of 81 genes whose expression levels are closely associated with increased cell longevity. Using expression data from ten independent sources, we found that these genes are more highly co-expressed in longer living tissues and are enriched in specific biological processes and transcription factors targets compared to randomly selected gene samples. Crucially, we found that PMCL-associated genes are down-regulated in the cerebral cortex and substantia nigra of Alzheimer’s and Parkinson’s disease patients as well as Hutchinson-Gilford progeria-derived fibroblasts, and that this down regulation is specifically linked to their underlying association with cellular longevity. Moreover, we found that sexually dimorphic brain expression of PMCL-associated genes reflects sexual differences in lifespan in humans and macaques. Taken together our results suggest that PMCL-associated genes are part of a generalized machinery of post-mitotic maintenance and functional stability in both neural and non-neural cells and support the notion of a common molecular repertoire differentially engaged in different cell types with different survival requirements.

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• Postmitotic cell longevity–associated genes: a transcriptional signature of postmitotic maintenance in neural tissues. (deposited 11 Jan 2019 13:47) [Currently Displayed]