PAX6 maintains β cell identity by repressing genes of alternative islet cell types

β Cells led astray by transcription factors and the company they keep

“…Thus, it is not surprising to find that NKX2.2 and PAX6 can serve as both activators and repressors of different genes in adult β cells (Figure 1, A and B). A further layer of complexity for deciphering the functions of NKX2.2 and PAX6 in the β cell transcriptome is evidenced by the finding that these TFs also exert regulatory effects on the activity and/or expression of other β cell-specific TFs, including PDX1, NKX6.1, NEUROD1, MAFA, and FOXA2 (8,9). The sequence context and, thus, the presence of other TFs bound to the same enhancer are likely to be major factors in determining the functional consequences of PAX6 and NKX2.2 binding (Figure 1, A and B).…”

“…NKX2.2 functions primarily as an activator of β cell genes (including TFs and glucose metabolic genes) and as a repressor of metabolically disallowed genes and genes expressed by other islet endocrine cell types (8). Similarly, Swisa and colleagues demonstrated that adult β cells lacking PAX6 also become partially transdifferentiated by acquiring ghrelin expression (9). PAX6 was found to function as both an activator and repressor, co-occupying enhancers bound by the β cell-specific TFs PDX1, NKX6.1, MAFA, FOXA2, and NEUROD1.…”

“…This knowledge will pave the way toward the development of new therapeutic approaches to prevent or reverse the progressive loss of functional β cell mass in patients with type 2 diabetes (T2D). In this issue, studies from the laboratories of Sussel (8), Dor (9), and Stoffers (10) collectively reinforce the consensus view that the same TFs that direct β cell specification are also required to maintain the gene activation and repression programs that undergird mature β cell identity (11)(12)(13)(14)(15). This unexpected property of the murine and human β cell transcriptional network provides an additional explanation for the intrinsic fragility, sensitivity (16), and propensity of these cells to adopt alternate endocrine cell fates as a consequence of various stressors (2,4,17).…”

“…TFs: maintenance of β cell identity on different levels β cell-specific ablation of Nkx2.2, Pax6, or Ldb1 in adult animals resulted in a similar suite of metabolic and physiologic defects in β cell function, including loss of insulin content, defects in insulin secretion, and glucose intolerance, with or without accompanying fasting or fed hyperglycemia (8)(9)(10). However, the underlying cause of these related phenotypes was found to be quite different in each case.…”

“…The studies on PAX6 and LDB1 indicate that they too fall into this category. Indeed, PAX6 mRNA and protein levels were downregulated in hyperglycemic insulin receptor antagonist-injected mice and in leptin receptor-deficient (db/db) mice in a manner that correlated with the age-dependent severity of hyperglycemia (9). Similarly, LDB1 mRNA and protein levels were also downregulated in db/db mice starting at 8 weeks of age (10).…”