During pancreas development, endocrine progenitors differentiate
into the islet-cell subtypes, which undergo further functional maturation in
postnatal islet development. In islet b-cells, genes
involved in glucose-stimulated insulin secretion are activated and glucose
exposure increases the insulin response as b-cells mature. Here, we investigated the role of H3K4 trimethylation
in endocrine cell differentiation and functional maturation by disrupting TrxG complex
histone methyltransferase activity in mouse endocrine progenitors. In the
embryo, genetic inactivation of TrxG component <i>Dpy30</i> in NEUROG3+ cells
did not affect the number of endocrine progenitors or endocrine cell
differentiation. H3K4 trimethylation was progressively lost in postnatal islets
and the mice displayed elevated non-fasting and fasting glycemia, as well as
impaired glucose tolerance by postnatal day 24. Although postnatal endocrine
cell proportions were equivalent to controls, islet RNA-sequencing revealed a
downregulation of genes involved in glucose-stimulated insulin secretion and an
upregulation of immature b-cell
genes. Comparison of histone modification enrichment profiles in NEUROG3+
endocrine progenitors and mature islets suggested that genes downregulated by
loss of H3K4 trimethylation more frequently acquire active histone
modifications during maturation. Taken together, these findings suggest that
H3K4 trimethylation is required for the activation of genes involved in the
functional maturation of pancreatic islet endocrine cells.
H3K4 Trimethylation is Required for Postnatal Pancreatic Endocrine Cell Functional Maturation
