J Clin Invest.
Human α cells display higher bivalency in genes encoding β cell transcriptional regulatory proteins.
(A) The epigenetic status of β cell signature genes (Figure 2B) functioning in ion transport or regulation of transcription was analyzed separately for α, β, and exocrine cells. Of the β cell–enriched ion transport genes, only 6% and 15% were marked bivalently in exocrine and β cells, respectively, while 29% carried this mark in α cells. For β cell signature genes involved in transcriptional regulation, 42% were marked as bivalent in α cells, but only 16% and 13% in β cells and exocrine cells, respectively. Thus α cells display a higher degree of bivalency for genes important in transcriptional regulation than for genes implicated in ion transport. (B and C) Schematic representation of the histone modification status of a relevant subset of human α and β cell signature genes (Figure 2B). The histone modification status of β cells is shown below each gene of interest. (B) As expected, most α cell signature genes are marked monovalently by H3K4me3 in α cells, and many of them carry a monovalent H3K27me3 mark in β cells. Interestingly, IRX1 and ARX are marked bivalently in α cells. (C) Within this subgroup of genes, β cell–expressed genes are marked monovalently by H3K4me3 in β cells, with the exception of HDAC9, which is marked bivalently. Remarkably, many β cell–expressed genes are marked bivalently in α cells, including the crucial insulin-synthesis enzyme PCSK1, the GLP1-receptor (GLP1R), and 2 essential β cell–specific transcription factors, MAFA and PDX1.