Foxa1 and Foxa2 Regulate α-Cell Differentiation, Glucagon Biosynthesis, and Secretion

Abstract

The Forkhead box A transcription factors are major regulators of glucose homeostasis. They show both distinct and redundant roles during pancreas development and in adult mouse β-cells. In vivo ablation studies have revealed critical implications of Foxa1 on glucagon biosynthesis and requirement of Foxa2 in α-cell terminal differentiation. In order to examine the respective role of these factors in mature α-cells, we used small interfering RNA (siRNA) directed against Foxa1 and Foxa2 in rat primary pancreatic α-cells and rodent α-cell lines leading to marked decreases in Foxa1 and Foxa2 mRNA levels and proteins. Both Foxa1 and Foxa2 control glucagon gene expression specifically through the G2 element. Although we found that Foxa2 controls the expression of the glucagon, MafB, Pou3f4, Pcsk2, Nkx2.2, Kir6.2, and Sur1 genes, Foxa1 only regulates glucagon gene expression. Interestingly, the Isl1 and Gipr genes were not controlled by either Foxa1 or Foxa2 alone but by their combination. Foxa1 and Foxa2 directly activate and bind the promoter region the Nkx2.2, Kir6.2 and Sur1, Gipr, Isl1, and Pou3f4 genes. We also demonstrated that glucagon secretion is affected by the combined effects of Foxa1 and Foxa2 but not by either one alone. Our results indicate that Foxa1 and Foxa2 control glucagon biosynthesis and secretion as well as α-cell differentiation with both common and unique target genes.

Integrated computational approach to the analysis of RNA-seq data reveals new transcriptional regulators of psoriasis

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MicroRNA single‐nucleotide polymorphisms and diabetes mellitus: A comprehensive review

“…Baroukh et al demonstrated that miR‐124a2 expression was significantly increased by the e18.5 stage through analysis of the miRNA expression profiles during the e14.5d and e18.5d stages (important periods of pancreatic cell differentiation) in mouse embryonic pancreases . FOXA2 (forkhead transcription factor A2) is a major regulator of pancreas development, islet cell differentiation, and glucagon synthesis . Baroukh et al demonstrated that gene expression levels of FOXa2 was decreased in mouse pancreatic tissue when transfected with miR‐124 precursors, whereas the expression of FOXa2 protein was increased in mice transfected with anti‐miR‐124a2.…”

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“…26 The combination of Foxa1 and Foxa2 (also known as hepatocyte nuclear factor (Hnf)) were shown to regulate Isl1 gene expression. 61 Hepatocyte nuclear factor (Hnf) family of transcription factors Several Hnf members have been implicated in the formation of the foregut endoderm from which the pancreas arises including Hnf1b, Hnf3b (hereafter called Foxa2) and Hnf6 (also called Onecut-1). [62][63][64][65] At e9.5, Hnf1b mutant mice lacked the ventral bud but a transient dorsal bud was present with temporal expression of Pdx1 and Hb9 (Table 1).…”