Molecular analysis of GTF2IRD1: a protein implicated in the neurobehavioural features of Williams-Beuren Syndrome

Williams-Beuren syndrome (WBS)is a complex neurodevelopmental disorder that results from a hemizygous deletion of 28 genes within human chromosome 7q11.23. WBS involves specific cognitive and behavioural features that are collectively called the Williams syndrome cognitive profile (WSCP) Genotype-phenotype correlations in patients with atypical deletions have implicated two members of the GTF2Iprotein family, GTF2IRD1and TFII-Iin the main aspects of the WSCP. We and others have generated Gtf2ird1 knockout mouse lines that show developmental and neurological abnormalities, social and non-social anxiety-related behavioural changes, reminiscent of the WSCP. In the mouse brain, Gtf2ird1 is expressed in a spatial pattern that largely overlaps with concentrations of GABAergic cell types, the major inhibitory neurons in the brain. However, the molecular function of GTF2IRD1is poorly understood. It was the aim of the work shown in this thesis to improve the understanding of molecular and cellular mechanisms of GTF2IRD1function, specifically by investigating i) potential target genes of GTF2IRD1through microarray analyses; ii) novel protein partners of GTF2IRD1via yeast-two hybrid screening and iii) the post-translational modification of GTF2IRD1by SUMOylation These studies have achieved their aims in a number of different ways. A lack of evidence for major transcriptional changes in the brains of Gtf2ird1 knockout mice and for directly regulated target genes has led to a reappraisal of the initial proposed function of GTF2IRD1as a conventional DNA-binding transcription factor. Instead, a role in chromatin remodeling is suggested by its interaction with novel proteins whose functions are associated with histone modification. Furthermore, this work has demonstrated that GTF2IRD1is modified by SUMOylation, which enhances its interaction with a chromatin-associated protein, ZMYMS. SUMOylation of GTF2IRD1, in itself, supports the newly proposed function of epigenetic regulation due to the extensive involvement of SUMOylation in chromatin biology. Epigenetic control through chromatin remodeling in the nervous system is rapidly growing as an important topic in the development of cognition, learning and neuropsychiatric disorders. The work in this thesis suggests that GTF21RD1 may contribute to these mechanisms and the disruption to such systems by GTF21RD1 absence may explain some of the neurobehavioural features of WBS