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.
Formation of new synapses, and alteration of the strength and stability of existing synapses are regarded as the main cellular basis for memory and long-term behavioral adaptations. Neuronal activity-regulated gene expression plays a crucial role in synaptic development and function, and its deregulation gives rise to various nervous system disorders. Knowledge about the regulatory mechanisms of activity-dependent gene expression is important both for understanding of nervous system function and for finding new drug targets. The aim of this project is to study the molecular mechanisms of neuronal activity-regulated gene expression, including transcription, translation and posttranslational modifications, in the nervous system health and disease. The studies are focused on two genes, the neurotrophin BDNF and the basic helix-loop-helix transcription factor TCF4.
"Pitt-Hopkins syndrome is a cognitive functional disorder, caused by a de novo genetic mutation of one allele of the transcription factor 4 (TCF4) gene. It has been reported that postnatal restoration of TCF functions in Pitt-Hopkins syndrome animal model (partially) rescues the phenotype, indicating that therapeutic approaches increasing TCF4 levels or activity might also help patients. It has also been reported that inhibiting histone deacetylase activity increases TCF4 transcriptional activity and rescues memory deficiencies associated with TCF4 haploinsufficiency in a mouse model. These effects are likely conveyed by some TCF4 co-repressor, such as ETO/RUNX1T1 recruiting HDACs. However, HDAC inhibitors have a very broad effect on the cellular transcription and can cause various side-effects.
Here, we hypothesize that by modulating the activity of specific TCF4 co-activators or co-repressors or their interaction with TCF4 could increase TCF4-dependent transcription, thus alleviating the symptoms of Pitt-Hopkins syndrome and have less side effects for the patients. To this end, we pursue to thoroughly identify the co-regulators participating in TCF4-dependent transcription, and to find means to modulate their activity. The specific aims are as follows: (1) Identify the co-regulatory proteins of different TCF4 protein isoforms. (2) Determine the mechanism of action and the interacting regions between TCF4 and co-regulatory proteins. (3) Develop means to modulate the transcriptional activity or binding of the TCF4 co-regulatory proteins."