Abstract for presentation at 11th International Congress of Human Genetics

Transcription regulation by GTF2IRD1 - A gene deleted in Williams-Beuren Syndrome

  • Pamela Thompson, University of Manchester, United Kingdom
  • Mr William Beckett, University of Manchester, United Kingdom
  • Mr Timothy Hinsley, University of Manchester, United Kingdom
  • Mrs Nichola Hart-Holden, University of Manchester, United Kingdom
  • Prof Andrew Sharrocks, University of Manchester, United Kingdom
  • Dr May Tassabehji, University of Manchester, United Kingdom

    • The purpose of this study was to illuminate the function of GTF2IRD1, one of a novel family of genes, all three members of which map to the region of chromosome 7q11.23 commonly deleted in Williams-Beuren syndrome (WBS). These genes are strongly implicated in phenotypic aspects of the disorder especially the cognitive and craniofacial features. The founder member of the family, TFII-I (or GTF2I), is known to regulate transcription through the initiator element (Inr), overlapping the transcription start site, and can also act through upstream DNA sequences including the E-box motif (CANNTG). The second member identified, GTF2IRD1, is also predicted to be a transcription factor, however, its mode of action is less clear. An initial analysis of upstream DNA sequences associated with GTF2IRD1 highlighted a conserved element we have termed ‘GUCE’ (GTF2IRD1 Upstream Control Element, 5’-GATTAW-3’), which is highly conserved upstream of three genes (HOXC8, GOOSECOID and TROPONIN ISLOW) in diverse animal species. In vitro gel retardation assays confirmed the GUCE sequence and showed that a specific domain of the GTF2IRD1 protein (I-4) is sufficient to mediate binding. Quantitative chromatin immunoprecipitation (ChIP) studies on the endogenous protein and luciferase assays demonstrate that GTF2IRD1 is associated with GUCE in vivo and can influence downstream transcription through this site. In addition, our data suggest that GTF2IRD1 may also regulate transcription through Inr elements at transcription start sites. In conclusion, we demonstrate a conserved DNA binding site for GTF2IRD1 and propose that this transcription factor may act, in a manner analogous to TFII-I, both through this upstream regulatory element while also influencing gene expression through the Inr element at the transcription start site.

    Conference Organiser - ICMS Pty Ltd