Kopp, N. D. | Search bioRxiv

bioRxiv2019

Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA-binding, and long term behavioral consequences.

Gtf2ird1 and Gtf2i may mediate aspects of the cognitive and behavioral phenotypes of Williams Syndrome (WS) - a microdeletion syndrome encompassing these transcription factors (TFs). Knockout mouse models of each TF show behavioral phenotypes. Here we identify their genomic binding sites in the developing brain, and test for additive effects of their mutation on transcription and behavior. Both TFs target constrained chromatin modifier and synaptic protein genes, including a significant number of ASD genes. They bind promoters, strongly overlap CTCF binding and TAD boundaries, and moderately overlap each other, suggesting epistatic effects. We used single and double mutants to test whether mutating both TFs will modify transcriptional and behavioral phenotypes of single Gtf2ird1 mutants. Despite little difference in DNA-binding and transcriptome-wide expression, Gtf2ird1 mutation caused balance, marble burying, and conditioned fear phenotypes. However, mutating Gtf2i in addition to Gtf2ird1 did not further modify transcriptomic or most behavioral phenotypes, suggesting Gtf2ird1 mutation alone is sufficient.

genetics↗

bioRxiv2019

Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region

Williams syndrome is a neurodevelopmental disorder caused by a 1.5-1.8Mbp deletion on chromosome 7q11.23, affecting the copy number of 26-28 genes. Phenotypes of Williams syndrome include cardiovascular problems, craniofacial dysmorphology, deficits in visual spatial cognition, and a characteristic hypersocial personality. There are still no genes in the region that have been consistently linked to the cognitive and behavioral phenotypes, although human studies and mouse models have led to the current hypothesis that the general transcription factor 2 I family of genes, GTF2I and GTF2IRD1, are responsible. Here we test the hypothesis that these two transcription factors are sufficient to reproduce the phenotypes that are caused by deletion of the Williams syndrome critical region (WSCR). We compare a new mouse model with loss of function mutations in both Gtf2i and Gtf2ird1 to an established mouse model lacking the complete WSCR. We show that the complete deletion model has deficits across several behavioral domains including social communication, motor functioning, and conditioned fear that are not explained by loss of function mutations in Gtf2i and Gtf2ird1. Furthermore, transcriptome profiling of the hippocampus shows changes in synaptic genes in the complete deletion model that are not seen in the double mutants. Thus, we have thoroughly defined a set of molecular and behavioral consequences of complete WSCR deletion, and shown that other genes or combinations of genes are necessary to produce these phenotypic effects.

animal behavior and cognition↗