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  3. A small-molecule inducer of PDX1 expression identified by high-throughput screening

A small-molecule inducer of PDX1 expression identified by high-throughput screening

  • Chem Biol. 2013 Dec 19;20(12):1513-22. doi: 10.1016/j.chembiol.2013.10.013.
Yuan Yuan 1,  Kate Hartland 2,  Zarko Boskovic 3,  Yikai Wang 4,  Deepika Walpita 4,  Philippe A Lysy 5,  Cheng Zhong 4,  Damian W Young 4,  Young-Kwon Kim 4,  Nicola J Tolliday 2,  Etienne M Sokal 5,  Stuart L Schreiber 3,  Bridget K Wagner 6
Affiliations

Affiliations

  • 1 Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
  • 2 Chemical Biology Platform, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 3 Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 4 Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • 5 Laboratory of Pediatric Hepatology and Cell Therapy, Catholic University of Leuven, Brussels 1200, Belgium.
  • 6 Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: [email protected].
PMID: 24290880 DOI: 10.1016/j.chembiol.2013.10.013
Abstract

Pancreatic and duodenal homeobox 1 (PDX1), a member of the homeodomain-containing transcription factor family, is a key transcription factor important for both pancreas development and mature β cell function. The ectopic overexpression of Pdx1, Neurog3, and MafA in mice reprograms acinar cells to insulin-producing cells. We developed a quantitative PCR-based gene expression assay to screen more than 60,000 compounds for expression of each of these genes in the human PANC-1 ductal carcinoma cell line. We identified BRD7552, which upregulated PDX1 expression in both primary human islets and ductal cells, and induced epigenetic changes in the PDX1 promoter consistent with transcriptional activation. Prolonged compound treatment induced both Insulin mRNA and protein and also enhanced Insulin expression induced by the three-gene combination. These results provide a proof of principle for identifying small molecules that induce expression of transcription factors to control cellular reprogramming.

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