A common cis-acting sequence in the DiGeorge critical region regulates bi-directional transcription of UFD1L and CDC45L

Two to three megabase deletions on chromosome 22q11 are the cytogenetic fin dings most commonly associated with cardiac and craniofacial defects in hum ans. The constellation of clinical findings associated with these deletions is termed the 22q11 deletion syndrome. We had earlier described a patient with the 22q11 deletion phenotype who was hemizygous for an atypical 20 kb microdeletion in this region. The deletion included coding regions of two g enes organized head-to-head, UFD1L and CDC45L, along with an 884 bp CpG-ric h intervening region. Based on this genomic organization, we hypothesized t hat both genes may be co-expressed and co-regulated by sequences within thi s region. We demonstrate that expression of both genes is enhanced in a sim ilar pattern in precursors of structures affected by the deletion. The inte rgenic region is sufficient to direct transcription most strongly in the de veloping pharyngeal arches and limb buds of transgenic mice and can also di rect bi-directional transcriptional activation in a neural crest-derived ce ll line. Deletion analyses revealed that a 404 bp fragment closest to UFD1L is necessary and sufficient to direct this bi-directional transcriptional activity. These results reveal the presence of a conserved regulatory regio n in the 22q11 deletion locus that can direct simultaneous transcription of genes involved in ubiquitin mediated protein processing (UFD1L) and cell c ycle control (CDC45L). (C) 2001 Elsevier Science Ireland Ltd. All rights re served.