Conserved C-terminal residues adjacent to the canonical PDX1 homeodomain are required for chromatin occupancy and pancreas development
12 affiliations
- 1Department of Cell & Developmental Biology, Vanderbilt University, Nashville, TN 37240, USA
- 2Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI 48109, USA
- 3Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37232, USA
- 4Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- 5Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA
- 6Department of Biological Sciences, Vanderbilt University, Nashville, TN 37240, USA
- 7Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- 8Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19105, USA
- 9Center for AI in Protein Dynamics, Vanderbilt University, Nashville, TN 37232, USA
- 10Department of Medicine, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- 11Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
- 12VA Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA
Abstract
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 (Pdx1Δ207). Despite normal protein levels, Pdx1Δ207 homozygous embryos exhibit severe pancreas hypoplasia by embryonic day (E)11.5, with particular impairment in endocrine differentiation. Although Pdx1Δ207 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.
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BibTeX
@article{wokasch2026conserved,
title = {{Conserved C-terminal residues adjacent to the canonical PDX1 homeodomain are required for chromatin occupancy and pancreas development}},
author = {Anthony S. Wokasch and Muhammad Shamoon and Courtney Campbell and Tianqi Wu and Jennifer D. Fuhr and Anna Gilbert and Thomas Mehaffey and Carter M. Barnes and Neha Ahuja and Morgan A. Gingerich and Jie Zhu and Paul Gadue and Ondine Cleaver and Hassane Mchaourab and Doris A. Stoffers and Scott A. Soleimanpour and Maureen Gannon},
journal = {Development (Cambridge, England)},
year = {2026},
month = oct,
doi = {10.1242/dev.205842},
url = {https://doi.org/10.1242/dev.205842},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Conserved C-terminal residues adjacent to the canonical PDX1 homeodomain are required for chromatin occupancy and pancreas development
AU - Anthony S. Wokasch
AU - Muhammad Shamoon
AU - Courtney Campbell
AU - Tianqi Wu
AU - Jennifer D. Fuhr
AU - Anna Gilbert
AU - Thomas Mehaffey
AU - Carter M. Barnes
AU - Neha Ahuja
AU - Morgan A. Gingerich
AU - Jie Zhu
AU - Paul Gadue
AU - Ondine Cleaver
AU - Hassane Mchaourab
AU - Doris A. Stoffers
AU - Scott A. Soleimanpour
AU - Maureen Gannon
PY - 2026
DA - 2026/10/20
JO - Development (Cambridge, England)
DO - 10.1242/dev.205842
UR - https://doi.org/10.1242/dev.205842
AB - 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 (Pdx1Δ207). Despite normal protein levels, Pdx1Δ207 homozygous embryos exhibit severe pancreas hypoplasia by embryonic day (E)11.5, with particular impairment in endocrine differentiation. Although Pdx1Δ207 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.
SN - 0950-1991
SN - 1477-9129
ER -