PDX1 is the cornerstone of pancreatic β-cell functions and identity

Abstract

Diabetes has been a worldwide healthcare problem for many years. Current methods of treating diabetes are still largely directed at symptoms, aiming to control the manifestations of the pathology. This creates an overall need to find alternative measures that can impact on the causes of the disease, reverse diabetes, or make it more manageable. Understanding the role of key players in the pathogenesis of diabetes and the related β-cell functions is of great importance in combating diabetes. PDX1 is a master regulator in pancreas organogenesis, the maturation and identity preservation of β-cells, and of their role in normal insulin function. Mutations in the PDX1 gene are correlated with many pancreatic dysfunctions, including pancreatic agenesis (homozygous mutation) and MODY4 (heterozygous mutation), while in other types of diabetes, PDX1 expression is reduced. Therefore, alternative approaches to treat diabetes largely depend on knowledge of PDX1 regulation, its interaction with other transcription factors, and its role in obtaining β-cells through differentiation and transdifferentiation protocols. In this article, we review the basic functions of PDX1 and its regulation by genetic and epigenetic factors. Lastly, we summarize different variations of the differentiation protocols used to obtain β-cells from alternative cell sources, using PDX1 alone or in combination with various transcription factors and modified culture conditions. This review shows the unique position of PDX1 as a potential target in the genetic and cellular treatment of diabetes.

Keywords: PDX1; diabetes; insulin; pancreas; β-cells.

FIGURE 1

Regulation of mammalian PDX1 gene by multiple factors. Expression of PDX1 is controlled by numerous epigenetic factors such as nucleosome positioning, histone methylation, histone acetylation, accessibility of enhancers and non-coding RNAs. PDX1 expression can be upregulated (bold green upward arrows) or downregulated (bold red downward arrows) by any of these factors. (A). Distant enhancers known as areas I-IV, participate in PDX1 transcription regulation due to their ability to bind transcription factors and boost gene expression. Same TFs can bind to multiple areas with different affinities, for example FOXA1/2 occupy area IV more efficiently (bold green arrows) than other areas (narrow green arrows). (B). regulation of PDX1 through upstream regulatory factors (USF) and E-box. (C). interaction of PDX1 and histone deacetylases. (D). interaction between β-arrestin-1, P300 and their role in PDX1 regulation. (E). PDX1 recruitment to Lys methyltransferase Set7/9. (F). RNA modification in PDX1 regulation. (G). (H). role of ncRNAs in PDX1 regulation.

FIGURE 2

Schematic representation of human β-cell maturation stages. β-Cell differentiation is a complex multistage process. In each stage cell populations have distinctive markers and require both activation (green upward arrows) and repression (red downward arrows) of different signaling pathways, transcription factors, hormones and small molecules.