Alex Sirp

"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."