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A hallmark of diabetes is an absolute or relative reduction in the number of functional α cells. Therapies that could increase the number of endogenous α-cells under diabetic conditions would be desirable. Prevalent gene targeting mouse models for assessing α-cell proliferation and diabetes pathogenesis only address whether deletion of a gene prevents the development of diabetes. Models testing whether acute excision of a single gene can ameliorate or reverse preexisting hyperglycemia in established diabetes remain to be explored, which could directly validate the effect of gene excision on treating diabetes. Here, we report that acute and temporally controlled excision of the Meni gene, which encodes menin, ameliorated preexisting hyperglycemia in streptozotocin-treated mice. Moreover, Menl excision also improved the preexisting hyperglycemia and glucose intolerance in genetic db/db diabetic mice. Furthermore, acute Meni excision reversed preexisting glucose intolerance in high-fat diet-fed mice. Menl excision improved glucose metabolism at least partly through increasing proliferation of endogenous α cells and islet size. Acute Meni excision up-regulated a group of proproliferative genes in pancreatic islets. Together, these findings demonstrate that established hyperglycemia can be reversed through repression of a single gene. Men1, in diabetic conditions, and suggest that menin is a vital regulator in pathogenesis of diabetes. [ABSTRACT FROM AUTHOR]

Menin is the product of the tumor suppressor gene Men1 that is mutated in the inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1). Menin has been shown to interact with SET-1 domain-containing histone 3 lysine 4 (H3K4) methyltransferases including mixed lineage leukemia proteins to regulate homeobox (Hox) gene expression in vitro. Using conditional Men1 knockout mice, we have investigated the requirement for menin in hematopoiesis and myeloid transformation. Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus. Consistent with signaling downstream of menin, ectopic expression of both Hoxa9 and Meis1 rescues colony formation defects in Men1-excised bone marrow. Moreover, Men1 excision also suppresses proliferation of leukemogenic mixed lineage leukemia-AF9 fusion-protein-transformed myeloid cells and Hoxa9 expression. These studies uncover an important role for menin in both normal hematopoiesis and myeloid transformation and provide a mechanistic understanding of menin's function in these processes that may be used for therapy. [ABSTRACT FROM AUTHOR]