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| Status |
Public on Jun 01, 2019 |
| Title |
The Pdx1 bound Swi/Snf chromatin remodeling complex regulates pancreatic progenitor cell proliferation and mature islet β cell function |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Transcription factors positively and/or negatively impact gene expression by recruiting coregulatory factors, which interact through protein-protein binding. Here we demonstrate that mouse pancreas size and islet β cell function are controlled by the ATP-dependent Swi/Snf chromatin-remodeling coregulatory complex that physically associates with Pdx1, a diabetes-linked transcription factor essential to pancreatic morphogenesis and adult islet-cell function and maintenance. Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia. In contrast, removal of both Swi/Snf ATPase subunits, Brg1 and Brm, were required to compromise adult islet β cell activity, which included whole animal glucose intolerance, hyperglycemia and impaired insulin secretion. Notably, lineage-tracing analysis revealed that these Swi/Snf deficient β cells lost the ability to produce insulin and other key metabolic genes, yet the expression levels of many essential islet-enriched transcription factors were unaffected. Swi/Snf was necessary for Pdx1 binding to the insulin enhancer, demonstrating the importance of this association in mediating chromatin accessibility. These results illustrate how fundamental the Pdx1:Swi/Snf coregulator complex is in the pancreas and we discuss how disrupting their association could influence Type 1 and Type 2 diabetes susceptibility.
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| Overall design |
Comparison of TdTomato flow-sorted Swi/Snf-deficient islet β cells to those from TdTomato flow-sorted control islet β cells
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| Contributor(s) |
Spaeth JM, Stein R |
| Citation missing |
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| Submission date |
Mar 27, 2019 |
| Last update date |
Jun 03, 2019 |
| Contact name |
Jason Spaeth |
| E-mail(s) |
jspaeth@iu.edu
|
| Phone |
3172748986
|
| Organization name |
Indiana University
|
| Department |
Pediatrics
|
| Lab |
MS2021
|
| Street address |
635 Barnhill Dr.
|
| City |
Indianapolis |
| State/province |
IN |
| ZIP/Postal code |
46202 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA529443 |
| SRA |
SRP189630 |
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