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TISSUE-SPECIFIC STEM CELLS

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

^aLaboratory of Molecular Biology and
^bClinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA

Key Words. Islet-derived precursor cells • Mesenchymal stromal cells • Epigenetic • Histone modifications • Insulin gene

Correspondence: Gary Felsenfeld, Ph.D., Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. Telephone: (301) 496-4173; Fax: (301) 496-0201; e-mail: gary.felsenfeld{at}nih.gov; or Marvin C. Gershengorn, Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. Telephone: (301) 496-4128; Fax: (301) 496-9943; e-mail: marving{at}intra.niddk.nih.gov

Received May 1, 2007; accepted for publication September 18, 2007.
First published online in STEM CELLS EXPRESS   September 27, 2007.



Human islet-derived precursor cells (hIPCs), mesenchymal cells derived in vitro from adult pancreas, proliferate freely and 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 with HeLa and human bone marrow-derived mesenchymal stem cells (hBM-MSCs), neither of which expresses 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 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.

Disclosure of potential conflicts of interest is found at the end of this article.

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				B. Davani, L. Ikonomou, B. M. Raaka, E. Geras-Raaka, R. A. Morton, B. Marcus-Samuels, and M. C. Gershengorn Human Islet-Derived Precursor Cells Are Mesenchymal Stromal Cells That Differentiate and Mature to Hormone-Expressing Cells In Vivo Stem Cells, December 1, 2007; 25(12): 3215 - 3222. [Abstract] [Full Text] [PDF]