The role of Ndy1 in epigenetic gene silencing and stem cell biology

Summary

Principal Investigator: Philip Tsichlis
Abstract: A genome wide screen for loci of common integration in MoMuLV-induced rat T cell lymphomas, led to the identification of a novel oncogene, Ndy1 (Not dead yet-1), also known as FBXL10, JHDM1B, or KDM2B, which is the subject of this proposal. Ndy1 encodes a 1336 amino acid chromatin-associated histone H3 demethylase, which contains an N-termal JmjC domain, a CXXC zinc finger domain, a PHD2 zinc finger, an F-box, and a leucine-rich repeat (LRR) and is expressed most highly in stem cells, such as embryonal stem cells (ES cells) and hematopoietic stem cells (HSCs). The demethylase activity of Ndy1 is specific for histone H3K36 (me2) and H3K4(me3) and it is JmjC domain-dependent. Our studies have linked Ndy1 to the induction of retrovirus-induced rodent hematopoietic neoplasms. Moreover, examination of its expression in existing databases has shown that Ndy1 is overexpressed in a variety of human tumors, primarily leukemias (AML and B and T cell leukemias), seminomas, and to a lesser extent, breast cancer. Studies from this laboratory have also shown that overexpression of Ndy1 inhibits both replicative and oncogene-induced senescence via a JmjC domain-dependent process and that its knockdown promotes senescence. Finally, its overexpression promotes genome wide epigenetic changes and alters the expression of genes involved in cell proliferation and survival. These data combined, suggest that Ndy1 is an oncogene that contributes to the development of human cancer. Other studies from this laboratory have shown that the expression of Ndy1 in ES stem cells, declines precipitously with differentiation and that exogenous Ndy1 expression in these ES cells interferes with, but does not completely block differentiation. These findings suggest that Ndy1 plays an important role in the cycling of stem cells. In agreement with these data, cells overexpressing Ndy1 are resistant to oxidative stress and hypoxia, features characteristic of stem cells. The proposed experiments will employ molecular biology and cell culture technologies, as well as bioinformatics and animal models to address the role of Ndy1 in the epigenetic regulation of gene expression and in the biology of stem cells.
Funding Period: ----------------2004 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via a JmjC domain-dependent process
    Raymond Pfau
    Molecular Oncology Research Institute, Tufts New England Medical Center, 75 Kneeland Street, Boston, MA 02111, USA
    Proc Natl Acad Sci U S A 105:1907-12. 2008
  2. pmc The JmjC domain histone demethylase Ndy1 regulates redox homeostasis and protects cells from oxidative stress
    Christos Polytarchou
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
    Mol Cell Biol 28:7451-64. 2008
  3. pmc The downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 axis and by human cytomegalovirus (HCMV) associated factors allows the activation of the HCMV major IE promoter and the transition to productive infection
    George Sourvinos
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America Laboratory of Virology, Medical School, University of Crete, Heraklion, Crete, Greece
    PLoS Pathog 10:e1004136. 2014
  4. pmc Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus
    Alexandros Tzatsos
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
    Proc Natl Acad Sci U S A 106:2641-6. 2009
  5. pmc Histone demethylases and cancer
    Sotirios C Kampranis
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA
    Adv Cancer Res 102:103-69. 2009
  6. pmc FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2B-miR-101-EZH2 pathway
    Filippos Kottakis
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
    Mol Cell 43:285-98. 2011

Detail Information

Publications6

  1. pmc Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via a JmjC domain-dependent process
    Raymond Pfau
    Molecular Oncology Research Institute, Tufts New England Medical Center, 75 Kneeland Street, Boston, MA 02111, USA
    Proc Natl Acad Sci U S A 105:1907-12. 2008
    ....
  2. pmc The JmjC domain histone demethylase Ndy1 regulates redox homeostasis and protects cells from oxidative stress
    Christos Polytarchou
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
    Mol Cell Biol 28:7451-64. 2008
    ..Simultaneous knockdown of Aass, Nqo1, Prdx4, and Serpinb1b in Ndy1-expressing cells to levels equivalent to those detected in control cells was sufficient to suppress the Ndy1 redox phenotype...
  3. pmc The downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 axis and by human cytomegalovirus (HCMV) associated factors allows the activation of the HCMV major IE promoter and the transition to productive infection
    George Sourvinos
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America Laboratory of Virology, Medical School, University of Crete, Heraklion, Crete, Greece
    PLoS Pathog 10:e1004136. 2014
    ..These data show that HCMV uses multiple mechanisms to allow the activation of the HCMV MIEP and to prevent cellular mechanisms from blocking the HCMV replication program. ..
  4. pmc Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus
    Alexandros Tzatsos
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
    Proc Natl Acad Sci U S A 106:2641-6. 2009
    ..Other studies show that, in addition to inhibiting replicative senescence, Ndy1 inhibits Ras oncogene-induced senescence via a similar molecular mechanism...
  5. pmc Histone demethylases and cancer
    Sotirios C Kampranis
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA
    Adv Cancer Res 102:103-69. 2009
    ..This review addresses the role of epigenetic modifications in cancer, focusing primarily on histone methylation marks and the enzymes catalyzing their removal...
  6. pmc FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2B-miR-101-EZH2 pathway
    Filippos Kottakis
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
    Mol Cell 43:285-98. 2011
    ..The FGF-2-NDY1/EZH2-miR-101-EZH2 axis described here was found to be active in bladder cancer. These data delineate an oncogenic pathway that functionally links FGF-2 with EZH2 via NDY1 and miR-101...