Molecular Basis of Williams-Beuren Syndrome: TFII-I Regulated Targets Involved in Craniofacial Development

Abstract

Objective The aim of this study is to identify gene targets of TFII-I transcription factors involved in craniofacial development. Design Recent findings in individuals with Williams-Beuren syndrome who show facial dysmorphism and cognitive defects have pointed to TFII-I genes ( GTF2I and GTF2IRD1) as the prime candidates responsible for these clinical features. However, TFII-I proteins are multifunctional transcriptional factors regulating a number of genes during development, and how their haploinsufficiency leads to the Williams-Beuren syndrome phenotype is currently unknown. Results Here we report the identification of three genes with a well-established relevance to craniofacial development as direct TFII-I targets. These genes, craniofacial development protein 1 ( Cfdp1), Sec23 homolog A ( Sec23a), and nuclear receptor binding SET domain protein 1 ( Nsd1), contain consensus TFII-I binding sites in their proximal promoters; the chromatin immunoprecipitation analysis showed that TFII-I transcription factors are recruited to these sites in vivo. Conclusions The results suggest that transcriptional regulation of these genes by TFII-I proteins could provide a possible genotype-phenotype link in Williams-Beuren syndrome.