Tõnis Timmusk

Neural plasticity is the ability of nervous system to change its activity in response to stimuli by reorganizing its structure, functions, or connections and this is the main cellular basis for memory. Activity-regulated genes play crucial roles in the formation of neuronal plasticity, and dysregulation of this process gives rise to various nervous system disorders. The neurotrophin BDNF is among the best-studied activity-regulated genes, and its polymorphisms are associated with impairments in human cognition. Our results also place the basic helix-loop-helix transcription factor TCF4, that is implicated in a variety of psychiatric and autism spectrum disorders, to the group of activity-regulated transcription factors. The aim of this project is to study gene regulation in intellectual disability and autism spectrum disorders with emphasis on disease-associated transcription factors TCF4, SATB2, FOXP1, and neurotrophin BDNF for finding new drug targets.

Enhancers are short distal cis-regulatory DNA regions that drive expression of a gene. However, enhancers do not function exclusively as DNA entities. Activated enhancers are transcribed by RNA polymerase II (RNAPII), which produces enhancer-derived RNAs (eRNAs). Production of eRNA creates additional trans-regulatory mechanisms facilitated by DNA-RNA, RNA-RNA, or protein-RNA interactions. Due to eRNAs’ fast degradation rates, and lack of robust and standardized sequencing methods, reports about the molecular nature of eRNA molecules and their processing are conflicting, making mechanisms of gene regulation by eRNA controversial. Even less is known about co- and post-transcriptional processing of eRNA. This project aims to overcome the controversy and fill the knowledge gap by studying a well-defined experimental system, cultured rat cortical neurons, and activation of immediate-early gene (IEG) response, perturbing the core eRNA endonuclease and combining this with eRNA-tailored sequencing, computational and biochemical methods. The developed integrative approach will reveal molecular features of eRNA molecules and their precursors genome-wide, opening the opportunity to study eRNA biogenesis to further understand molecular mechanisms behind the eRNA-mediated gene regulation.

Astrocytes comprise one of the main cell types in the central nervous system (CNS), and it is now recognized that they have important roles in ensuring proper development and homeostasis of the CNS, with astrocyte dysfunction contributing to all major neurological disorders. Recent studies have shown that these cells undergo dramatic transcriptional changes in response to neuron-derived stimuli. However, what are the astrocyte-specific mechanisms that regulate these changes are still largely unknown. Here, this issue will be tackled using state-of-the art functional genomic approaches to generate a comprehensive map of the astrocyte-specific regulatory elements (with a focus on enhancers) and transcription factors that govern stimuli-induced gene expression changes. This will provide unique and original insights into the mechanisms that control stimuli-induced gene expression in non-neuronal CNS cells, with potential implications for the understanding of several neuropathologies.