Regulation of FoxA2 gene expression: identification and characterization of two alternate gene transcripts

The main function of pancreatic beta cells is secretion of insulin in response to changing blood nutrients, to maintain metabolic homeostasis. Pancreas development and mature beta cell function are controlled by precisely timed signaling events and hierarchical gene expression. In turn, this is controlled by key transcription factors, such as the master regulator FoxA2, which acts as a pioneer transcription factor that is essential for endoderm development and function. Although the actions of the FoxA2 protein have been relatively well studied, regulation of the gene remains poorly understood. While trying to elucidate the regulation of the FoxA2 gene in adult cells and in development, we identified a novel FoxA2 gene transcript controlled by a distinct promoter that we functionally characterized. Surprisingly, the novel transcript is expressed at higher levels than the canonical transcript in all tissues examined, with the sole exception of liver. We demonstrated that the ratio of the transcripts among different FoxA2-expressing tissues, is probably due to differential strengths of the two promoters, and not to RNA stability. The novel transcript encodes a predicted protein that is 6 amino acids longer than the canonical FoxA2 protein. We showed that these protein isoforms have similar functional activities, and that the FoxA2 protein can auto-regulate its own promoter in a cell-specific manner. Determining the biological significance of each transcript and further analysis of FoxA2 gene regulation will lead to better understanding of beta cell development and function, and the role of this gene in controlling transcriptional programs in different organs.