Maintenance of neuronal identity and function

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.

List of scientific papers

I. A comprehensive map coupling histone modifications with gene regulation in adult dopaminergic and serotonergic neurons. Erik Södersten, Konstantinos Toskas, Vilma Rraklii, Katarina Tiklova, Åsa K Björklund, Markus Ringnér, Thomas Perlmann, Johan Holmberg Nature Communications. 2018 Mar 26;9(1):1226.
https://doi.org/10.1038/s41467-018-03538-9

II. PRC2-mediated repression is essential to maintain identity and function of differentiated dopaminergic and serotonergic neurons. Konstantinos Toskas, Behzad Yaghmaeian-Salmani, Olga Skiteva, Wojciech Paslawski, Linda Gillberg, Vasiliki Skara, Irene Antoniou, Erik Södersten, Per Svenningsson, Karima Chergui, Markus Ringnér, Thomas Perlmann, Johan Holmberg. [Manuscript]

III. Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2a to tumor suppression. Isabelle Westerlund, Yao Shi, Konstantinos Toskas, Stuart M.Fell, Shuijie Li, Olga Surova, Erik Södersten, Per Kogner, Ulrika Nyman, Susanne Schlisio, Johan Holmberg. PNAS. 2017 Jul 25;114(30):E6137-E6146.
https://doi.org/10.1073/pnas.1700655114