title: A small-molecule inducer of PDX1 expression identified by high-throughput screening.
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.
authors.affiliation: 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.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Chemical Biology Platform, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Hartland
authors.affiliation: 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.
authors.forename: Zarko
authors.initials: Z
authors.lastname: Boskovic
authors.affiliation: Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Yikai
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Deepika
authors.initials: D
authors.lastname: Walpita
authors.affiliation: Laboratory of Pediatric Hepatology and Cell Therapy, Catholic University of Leuven, Brussels 1200, Belgium.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Lysy
authors.affiliation: Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Damian W
authors.initials: DW
authors.lastname: Young
authors.affiliation: Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Young-Kwon
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Chemical Biology Platform, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Tolliday
authors.affiliation: Laboratory of Pediatric Hepatology and Cell Therapy, Catholic University of Leuven, Brussels 1200, Belgium.
authors.forename: Etienne M
authors.initials: EM
authors.lastname: Sokal
authors.affiliation: 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.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: bwagner@broadinstitute.org.
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Wagner
mesh_terms: D000818:Animals; D044584:Carcinoma, Ductal / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D057166:High-Throughput Screening Assays / Q000379:methods; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D018398:Homeodomain Proteins; D054852:Small Molecule Libraries; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein