Ginsburg Lab
Jill M. Johnsen, MD
Clinical Lecturer, Hematology & Oncology
Research Interests
The regulation of endothelial cell gene expression plays a central role in maintaining hemostatic balance. However, little is known about the key sequence elements responsible for the control of the endothelial gene expression program. We previously identified the cause of low levels of von Willebrand factor (VWF) in the inbred mouse strain RIIIS/J as a regulatory mutation in the gene encoding an N-acetylgalactosaminyltransferase, GALGT2. This low VWF allele, which we termed Mvwf1, results from a tissue-specific switch in expression program from intestinal epithelium to vascular endothelium. The ectopic expression of Galgt2 in vascular endothelial cells results in aberrant post-translational modification of VWF, leading to accelerated clearance. We have narrowed the genomic region responsible for intestinal Galgt2 expression using an overlapping BAC transgenic strategy. Comparative sequence analysis of 10 independent Mvwf1 strains has identified a large shared haplotype block containing a region of high sequence divergence flanking the Galgt2 transcriptional start site. This Mvwf1 haplotype block overlaps the interval conferring wild-type expression, indicating that this region likely contains the regulatory elements necessary for tissue-specific Galgt2 gene expression. We are now recombineering chimeric RIIIS/J:C57BL6/J BACs to pinpoint the regions critical for endothelial cell-specific gene regulation.
