Maintenance of neuronal identity and function

Abstract

Neurons in the CNS acquire specific characteristics throughout development and maintain them for the entire lifespan. Instructive regulation of the transcription machinery ensures the acquisition of identity by spatiotemporal patterns of transcription factor expression. Additionally, gene silencing of alternative lineages is important for specification of neuronal identity and function, however the mechanisms regulating transcriptional repression are poorly understood. In this study we focused on epigenetic regulation of gene expression and how perturbation of it can lead to loss of function and disease.

In Paper I we characterized histone modifications on two clinically relevant neuronal populations, the dopaminergic and serotonergic neurons implicated in Parkinson’s disease and depression respectively. We studied the repressive modifications H3K27me3, H3K9me3 and active H3K4me3 and associated them with gene expression levels throughout cell maturation, from NPCs to adult postmitotic neurons. The generated comprehensive map also illustrates how drug induced stress in dopaminergic neurons alters the histone modifications pattern affecting gene expression.

After acquisition of identity, Paper II focuses on how this can be maintained throughout life. Removal of H3K27me3 in dopaminergic and serotonergic neurons resulted to erroneous gene expression patterns and progressive loss of neuronal function. In dopaminergic neurons electrophysiological and molecular properties were perturbed in a region specific manner, with SNc being the most vulnerable, phenomenon similar to PD development. Mice showed phenotypic impairments with motor symptoms or anxiety-like behavior in cell-type dependent manner.

In Paper III DNA methylation in neuroblastoma tumors was examined as a potential therapeutic approach. Hypermethylated loci keep potential tumor suppressors silenced leading to cancer formation. Here we showed that combined administration of the demethylating AZA with RA that promotes neuronal differentiation exhibited a favorable outcome in tumor growth. Further analysis of treated xenografted tumors revealed EPAS1 as a potential tumor suppressor, opposite to previously published data assigning the gene as an oncogene.