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A small-molecule inducer of PDX1 expression identified by high-throughput screening
Yuan Yuan1, Kate Hartland2, Zarko Boskovic3
1Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Chemistry & Biology
|December 3, 2013
Summary
Researchers screened compounds to find molecules that boost PDX1 expression, a key factor for pancreas development and beta cell function. One compound, BRD7552, successfully upregulated PDX1 and enhanced insulin production, showing potential for cellular reprogramming.
Area of Science:
- Endocrinology
- Molecular Biology
- Cellular Reprogramming
Background:
- Pancreatic and duodenal homeobox 1 (PDX1) is crucial for pancreas development and beta cell function.
- Ectopic expression of Pdx1, Neurog3, and MafA can reprogram acinar cells into insulin-producing cells.
Purpose of the Study:
- To identify small molecules that can upregulate PDX1 expression.
- To investigate the potential of these molecules in cellular reprogramming for enhanced insulin production.
Main Methods:
- Developed a quantitative PCR-based gene expression assay.
- Screened over 60,000 compounds using the human PANC-1 ductal carcinoma cell line.
- Assessed compound effects on PDX1 expression, epigenetic changes, and insulin production in human islets and ductal cells.
Main Results:
- Identified BRD7552 as a compound that upregulates PDX1 expression in human islets and ductal cells.
- BRD7552 induced epigenetic changes in the PDX1 promoter, indicating transcriptional activation.
- Prolonged treatment with BRD7552 enhanced insulin mRNA and protein levels, and boosted insulin expression induced by the three-gene combination.
Conclusions:
- Demonstrated a proof-of-principle for using small molecules to induce transcription factor expression for cellular reprogramming.
- BRD7552 shows potential for therapeutic strategies aimed at restoring beta cell function or generating insulin-producing cells.
