Figure 1.

Epigenetic control in early pancreas development and endocrine cell fate allocation.

During early endoderm development into liver and pancreas fates, liver-specific genes and pancreas-specific genes are differentially marked in multipotent cells. While PDX1, and early pancreatic gene, is bivalently marked with both the activation-associated H3K9acK14ac histone modification and H3K27me3, associated with gene silencing, liver-specific genes such as Alb1, Afp and Ttr carry none of these histone marks. Upon differentiation into hepatoblasts, the H3K9acK14ac mark increases on liver-specific promoters, while H3K27me3 remains low, whereas the PDX1 promoter remains hyperacetylated and enriched for H3K27me3. These cell fate programs are modulated by the histone acetyltransferase P300, and by Ezh2, a methyltransferase for H3K27me3. During pancreatic islet development, the α and β-cells fate decision is epigenetically regulated by the differentially recruitment of a repression complex (DNMT3a, Grg3 and HDAC1) by Nkx2.2, to the Arx gene promoter in β-cells, but not α–cells. This differential binding is influenced by the methylation state of the Arx promoter.

In post-natal life, the maintenance of α and β-cell identity is epigenetically regulated by a differentially methylated state of part of the Arx promoter. In β-cells, this region is hypermethylated, and is occupied by a repressive complex of MeCP2 and PRMT6, to repress the Arx locus. In α-cells, this promoter region is kept hypomethylated.