Abstract
Jarid2 is a component of the Polycomb Repressor complex 2 (PRC2), which is responsible for genome-wide H3K27me3 deposition, in embryonic stem cells. However, Jarid2 has also been shown to exert pleiotropic PRC2-independent actions during embryogenesis. Here, we have investigated the role of Jarid2 during pancreas development. Conditional ablation of Jarid2 in pancreatic progenitors results in reduced endocrine cell area at birth due to impaired endocrine cell differentiation and reduced prenatal proliferation. Inactivation of Jarid2 in endocrine progenitors demonstrates that Jarid2 functions after endocrine specification. Furthermore, genome-wide expression analysis reveals that Jarid2 is required for the complete activation of the insulin-producing β-cell differentiation program. Jarid2-deficient pancreases exhibit impaired deposition of RNAPII-Ser5P, the initiating form of RNAPII, but no changes in H3K27me3, at the promoters of affected endocrine genes. Thus, our study identifies Jarid2 as a fine-tuner of gene expression during late stages of pancreatic endocrine cell development. These findings are relevant for generation of transplantable stem cell-derived β-cells.
Highlights
Diabetes mellitus (DM) is a complex disease that results from failure of β-cells to secrete enough insulin to maintain normoglycemia
Between embryonic day (e)13.5 and e15.5, the bulk of endocrine cell formation unfolds in the trunk region of the pancreatic epithelium, a process known as the secondary transition
The remaining Jarid[2] expression is possibly due to non-recombined epithelial cells and non-epithelial cell types, such as mesenchymal cells, which are present in reduced proportion as the pancreas develops[21]
Summary
Diabetes mellitus (DM) is a complex disease that results from failure of β-cells to secrete enough insulin to maintain normoglycemia. Transient expression of the master pro-endocrine transcription factor Neurogenin[3] (Ngn3) in discrete cells within this domain generates monohormonal endocrine precursors, which will activate genes necessary for their endocrine function as they become mature endocrine cell types. H3K27me[3] is dynamically modified at the promoters of pancreatic and endocrine-specific genes[7, 8]. In mouse pancreatic explants and pancreatic cells obtained from hESCs, chemical inhibition of Ezh[2] resulted in increased endocrine cell differentiation[8]. Two studies aimed at identifying genes enriched during pancreatic endocrine differentiation in vivo in mouse embryos, reported increased expression of Jarid[2] in endocrine progenitors and descendants[19, 20]. We show that Jarid[2] is required in progenitor cells to activate the β-cell gene expression program and generate fully differentiated β-cells
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