The Human Insulin Gene Displays Transcriptionally Active Epigenetic Marks in Islet-derived Mesenchymal Precursor Cells in the Absence of Insulin Expression

¹ Laboratory of Molecular Biology NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA
² Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA

^* To whom correspondence should be addressed. E-mail: marving{at}intra.niddk.nih.gov.

	Abstract

Human islet-derived precursor cells (hIPCs), mesenchymal cells derived in vitro from adult pancreas, proliferate freely, do not express insulin but can be differentiated to epithelial cells that express insulin. hIPCs have been studied with the goal of obtaining large quantities of insulin producing cells suitable for transplantation into patients suffering from type 1 diabetes. It appeared that undifferentiated hIPCs are "committed" to a pancreatic endocrine phenotype through multiple cell divisions, suggesting that epigenetic modifications at the insulin locus could be responsible. We determined patterns of histone modifications over the insulin gene in human islets and hIPCs, and compared them to HeLa and human bone marrow-derived mesenchymal stem cells (hBM-MSCs), neither of which express insulin. The insulin gene in islets displays high levels of histone modifications (H4 hyperacetylation and dimethylation of H3 lysine 4) typical of active genes. These are not present in HeLa and hBM-MSCs, which instead have elevated levels of H3 lysine 9 dimethylation, a mark of inactive genes. hIPCs, in contrast, show significant levels of active chromatin modifications, as much as half those seen in islets, and show no measurable H3 K9 methylation. Cells expanded from a minor population of mesenchymal stromal cells (MSCs) found in islets exhibit the same histone modifications as established hIPCs. We conclude that hIPCs, which do not express the insulin gene, nonetheless uniquely exhibit epigenetic marks that could poise them for activation of insulin expression. This epigenetic signature may be a general mechanism whereby tissue-derived precursor cells are committed to a distinct specification.

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