A Chromatin-Associated Histone H3 Dementhylase Promotes the Immortalization of MEFs and the Cycling of HSC-Like Cells in Culture.

A common integration site, cloned from MoMuLV-induced rat T cell lymphomas was mapped immediately upstream of Ndy1, a gene expressed primarily in ES cells, hematopoietic stem cells, testis, spleen and thymus. Ndy1 encodes a chromatin-associated nuclear protein. Ndy1 and its homolog Ndy2, which is also a target of provirus integration in retrovirus-induced lymphomas, encode proteins that were recently shown to possess JmjC-dependent histone H3 demethylase activity. Mouse embryo fibroblasts (MEFs) engineered to express Ndy1 or Ndy2 undergo immortalization in the absence of replicative senescence via a JmjC domain-dependent process. Knock down of endogenous Ndy1 or expression of JmjC domain mutants of Ndy1 promotes senescence, suggesting that Ndy1 is a physiological inhibitor of senescence in dividing cells. Infection of bone marrow cells with a high titer MigR1/Ndy1 retrovirus led to the reproducible isolation of immortalized cultures that have the phenotypic characteristics of hematopoietic stem cells. We conclude that Ndy-mediated demethylation of histone H3, promotes cell immortalization, oncogenesis and the cycling of stem cells.