Role of transcription factors in the transdifferentiation of pancreatic islet cells

Abstract

The α and β cells act in concert to maintain blood glucose. The α cells release glucagon in response to low levels of glucose to stimulate glycogenolysis in the liver. In contrast, β cells release insulin in response to elevated levels of glucose to stimulate peripheral glucose disposal. Despite these opposing roles in glucose homeostasis, α and β cells are derived from a common progenitor and share many proteins important for glucose sensing and hormone secretion. Results from recent work have underlined these similarities between the two cell types by revealing that β-to-α as well as α-to-β transdifferentiation can take place under certain experimental circumstances. These exciting findings highlight unexpected plasticity of adult islets and offer hope of novel therapeutic paths to replenish β cells in diabetes. In this review, we focus on the transcription factor networks that establish and maintain pancreatic endocrine cell identity and how they may be perturbed to facilitate transdifferentiation.

Keywords: ARX; FOXO1; NKX2-2; PAX4; PDX1; dedifferentiation; diabetes; transdifferentiation; α cell; β cell.

Figure 1

Development and maintenance of alpha and beta cells from a common progenitor (A) requires intricate networks of transcription factors. Transcription factors and hormones specific to beta (red) and alpha (green) cells are indicated. Despite their opposing functions in the regulation of blood glucose levels, alpha and beta cells continue to share the expression of many transcription factors (black). Specificity of gene expression was determined by significant (p<10⁻⁷) enrichment in one cell type over the other (B). This figure was adapted with permission from (Benner et al. 2014).

Figure 2

Illustration of the pancreatic transcription networks in alpha and beta cells. Expression of transcription factors PDX1(A), NKX2.2 (B), NKX6.1 (C), NEUROD1 (D), MAFA (E), PAX4 (F), ARX (G) and FOXO1 (H) in beta and alpha cells by whole transcriptome sequencing (RNA-Seq), combined with chromatin immuno-precipitation data (ChIP-Seq) for PDX1 (Khoo, et al. 2012), NKX6.1 (Taylor et al. 2013) and NEUROD1 and MAFA (Tennant, et al. 2013). Purple arrowheads indicate binding of NKX6.1 and PDX1 to the same TAAT sequence in the NKX6.1 gene, green arrow heads point to closely spaced but non-identical binding sites for NEUROD1, NKX6.1 and PDX1 on the NEUROD1 and MAFA genes. Blue arrow heads indicate the PDX1 and NKX6.1 binding site on the ARX gene. NKX6.1 inhibits ARX expression via this interaction (Schaffer et al. 2013).