In silico gene expression and pathway analysis of DEK in the human brain across the lifespan

Abstract

DEK, a chromatin-remodelling phosphoprotein, is associated with various functions and biological pathways in the periphery, including inflammation, oncogenesis, DNA repair, and transcriptional regulation. We recently identified an association between DEK loss and central nervous system diseases, such as Alzheimer's. To understand DEK's potential role in disease, it is critical to characterize DEK in healthy human brain to distinguish between neural DEK expression and function in healthy versus diseased states like dementia.We utilized two public databases, BrainCloud and Human Brain Transcriptome, and analysed DEK mRNA expression across the lifespan in learning and memory relevant brain regions. Since DEK loss induces phenotypes associated with brain ageing (e.g., DNA damage and apoptosis), we hypothesized that neural DEK expression may be highest during foetal development and lower in elderly individuals. In agreement with this hypothesis, DEK was most prominently expressed during foetal development in all queried forebrain areas, relative to other ages. Consistent with its roles in the periphery, pathways related to DEK in the brain were associated with cellular proliferation, DNA replication and repair, apoptosis, and inflammation. We also found novel neural development-relevant pathways (e.g., synaptic transmission, neurite outgrowth, and myelination) to be enriched from genes correlated with DEK expression. These findings suggest that DEK is important for human brain development. Overall, we highlight age-related changes in neural DEK

Novel molecular mechanisms in Alzheimer’s disease: The potential role of DEK in disease pathogenesis

“…We observed sex differences in DEK expression in the demented human brain but not in the healthy brain (O'Donovan et al, 2018;Greene et al, 2022). DEK is known to be a target gene of sex hormone receptors (Privette Vinnedge et al, 2012), and hormone regulation and signaling have been identified as DEK-associated pathways in the human brain (Greene et al, 2022). Therefore, it will be important to consider the potential sex-specific effect of DEK loss in AD and other age-related dementias.…”

“…First, we do not know how DEK loss could impact neurodegeneration differently in males and females. We observed sex differences in DEK expression in the demented human brain but not in the healthy brain (O'Donovan et al, 2018;Greene et al, 2022). DEK is known to be a target gene of sex hormone receptors (Privette Vinnedge et al, 2012), and hormone regulation and signaling have been identified as DEK-associated pathways in the human brain (Greene et al, 2022).…”

“…We confirmed these findings in humans, using data from online tools such as Brain RNA-Seq and Human Protein Atlas. DEK is expressed in most major cell types, including astrocytes, microglia, oligodendrocytes, endothelial cells, and neurons ( Greene et al, 2022 ). DEK expression is approximately two to three-fold higher in fetal astrocytes than other cell types analyzed, followed by relatively high expression levels in microglia and oligodendrocytes ( Greene et al, 2022 ).…”

“…DEK is expressed in most major cell types, including astrocytes, microglia, oligodendrocytes, endothelial cells, and neurons ( Greene et al, 2022 ). DEK expression is approximately two to three-fold higher in fetal astrocytes than other cell types analyzed, followed by relatively high expression levels in microglia and oligodendrocytes ( Greene et al, 2022 ). DEK expression levels are similar in neurons, mature astrocytes, and endothelial cells ( Greene et al, 2022 ).…”

“…DEK expression is approximately two to three-fold higher in fetal astrocytes than other cell types analyzed, followed by relatively high expression levels in microglia and oligodendrocytes ( Greene et al, 2022 ). DEK expression levels are similar in neurons, mature astrocytes, and endothelial cells ( Greene et al, 2022 ). In addition, DEK is expressed in the human forebrain, midbrain, and hindbrain; the areas with the highest DEK RNA expression are the cerebellum, thalamus, and cerebral cortex ( Greene et al, 2022 ).…”