Structural impotence of PDX-1 protein in the epigenetic control of insulin expression

Abstract

This study investigates the role of pancreatic and duodenal homeobox 1 (PDX-1) as an important transcription factor in the epigenetic regulation of insulin expression. The research focused on PDX-1 as a disordered protein, and how the flexibility of its intrinsically disordered regions (IDRs) allows PDX-1 to interact with various transcription factors and epigenetic enzymes, facilitating histone modifications and insulin transcription. Particularly, the role of PDX-1 in processes like acetylation, methylation, and demethylation was discussed by detailing its interactions with key enzymes such as p300, Set7, and JMJD3. For instance, PDX-1’s interaction with p300 leads to histone H4 hyperacetylation, enhancing insulin gene expression, while Set7-mediated methylation of H3K4 further promotes transcription. In addition, the demethylation of H3K27 by JMJD3 is also facilitated by the PDX-1 protein. Finally, structural predictions of PDX-1 using AlphaFold III and EMS Fold also highlight the importance of its IDRs in these interactions. The findings highlight the significance of PDX-1 in insulin regulation and offer insights into potential therapeutic targets for treating diabetes from an epigenetic approach.