Investigations into islet pdx1 activity: contribution to mature β-cell identity and the identification and characterization of Pdx1 coregulators

Abstract

Pdx1 is a transcription factor of fundamental importance to pancreas formation and adult islet β-cell function. However, little is known regarding its role in mature β-cells or the positive- and negative-acting coregulators recruited to mediate transcriptional control. Using a conditional deletion and lineage tracing strategy we revealed a bifunctional role of Pdx1 in maintenance of mature β-cell identity as Pdx1-deleted cells rapidly lost β-cell features and simultaneously acquired a global transcriptional profile similar to β-cells. To better understand how Pdx1 mediates its actions in mature β-cells, a coimmunoprecipitation/mass spectrometry approach was undertaken. Numerous Pdx1-interacting factors possessing a wide range of cellular functions linked with this protein, including, but not limited to, coregulators associated with transcriptional activation and repression, DNA damage response, and DNA replication were isolated. Because chromatin remodeling activities are essential to developmental lineage decisions and adult cell function, our analysis focused on investigating the influence of the Swi/Snf chromatin remodeler on Pdx1 action.