Conserved C-terminal residues adjacent to the canonical PDX1 homeodomain are required for chromatin occupancy and pancreas development.

Essential roles for the PDX1 transcription factor in pancreatic development and β-cell function are well-known, yet the structure-function relationships of domains within its C-terminus remain incompletely defined. We identified a focal intrinsically disordered region (IDR) spanning residues 207-223 of the Pdx1 C-terminus and generated mice harboring deletion of this region (Pdx1▵207). Despite normal protein levels, Pdx1▵207 homozygous embryos exhibit severe pancreas hypoplasia by embryonic day (E)11.5, with particular impairment in endocrine differentiation. Although Pdx1▵207 localization was predominantly nuclear in β cells, further biochemical analyses revealed loss of chromatin occupancy at PDX1 target genes and decreased transcriptional activation of the Ins2 promoter. Truncation of the C-terminus beginning at residue 211 had no effect on target gene occupancy, localizing the functional requirement to highly conserved residues 207-210. Interestingly, structural predictions suggest that residues 207-210 incorporate into an extended helical structure immediately adjacent to the PDX1 homeodomain, suggesting potential conformational transitions within this IDR. Taken together, these four conserved residues are required for optimal PDX1 chromatin occupancy and pancreas organogenesis.