PT  - JOURNAL ARTICLE
AU  - Nathan D. Kopp
AU  - Kayla R. Nygaard
AU  - Katherine B. McCullough
AU  - Susan E. Maloney
AU  - Harrison W. Gabel
AU  - Joseph D. Dougherty
TI  - Functions of <em>Gtf2i</em> and <em>Gtf2ird1</em> in the developing brain: transcription, DNA-binding, and long term behavioral consequences
AID  - 10.1101/854851
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 854851
4099  - http://biorxiv.org/content/early/2019/11/25/854851.short
4100  - http://biorxiv.org/content/early/2019/11/25/854851.full
AB  - 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.