Gtf2ird1 and Gtf2i are two transcription factors (TFs) among the 28 genes deleted in Williams syndrome, and prior 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. GTF2IRD1 binding targets were enriched for transcriptional and chromatin regulators and mediators of ubiquitination. GTF2I targets were enriched for signal transduction proteins, including regulators of phosphorylation and WNT. Both TFs are highly enriched at promoters, strongly overlap CTCF binding and topological associating domain boundaries and moderately overlap each other, suggesting epistatic effects. Shared TF targets are enriched for reactive oxygen species-responsive genes, synaptic proteins and transcription regulators such as chromatin modifiers, including a significant number of highly constrained genes and known ASD genes. We next used single and double mutants to test whether mutating both TFs will modify transcriptional and behavioral phenotypes of single Gtf2ird1 mutants, though with the caveat that our Gtf2ird1 mutants, like others previously reported, do produce low levels of a truncated protein product. Despite little difference in DNA binding and transcriptome-wide expression, homozygous 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 was sufficient for the observed phenotypes.

中文翻译：

---

Gtf2i 和 Gtf2ird1 在发育中的大脑中的功能：转录、DNA 结合和长期行为后果。

Gtf2ird1和Gtf2i是威廉姆斯综合征中缺失的 28 个基因中的两个转录因子 (TF)，并且每个 TF 的先前小鼠模型显示行为表型。在这里，我们确定了它们在发育中的大脑中的基因组结合位点，并测试了它们的突变对转录和行为的附加影响。GTF2IRD1 结合靶标富含转录和染色质调节因子以及泛素化介质。GTF2I 靶标富含信号转导蛋白，包括磷酸化和 WNT 的调节剂。两个 TF 在启动子处高度富集，与 CTCF 结合和拓扑关联域边界强烈重叠，彼此适度重叠，表明上位效应。共享的 TF 目标富含活性氧响应基因、突触蛋白和转录调节因子，如染色质修饰剂、包括大量高度受限的基因和已知的 ASD 基因。我们接下来使用单突变体和双突变体来测试突变两个 TF 是否会改变单突变体的转录和行为表型。Gtf2ird1突变体，但需要注意的是，我们的Gtf2ird1突变体，就像之前报道的其他突变体一样，确实会产生低水平的截断蛋白质产物。尽管 DNA 结合和转录组范围内的表达几乎没有差异，但纯合子Gtf2ird1突变导致平衡、大理石埋藏和条件恐惧表型。然而，变异Gtf2i除了Gtf2ird1没有进一步修改转录或大部分行为表型，提示Gtf2ird1突变独显足以观察到的表型。