title: [Functional analysis of TET2 using a knockdown mouse model].
abstract: In myeloid malignancies, mutations have occurred in epigenetic regulator genes, including Ten-Eleven-Translocation 2 (TET2). TET2 is an enzyme that catalyzes the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5-hmC) which is a key intermediate for oxidative DNA demethylation. We analyzed the in vivo phenotype of TET2 failure using Ayu17-449 (TET2(trap/trap)) mice created by the gene-trap method in which TET2 mRNA levels were decreased to about 20% of the level in wild-type (WT) mice. In TET2(trap/trap) mice the levels of 5-hmC in genomic DNA from bone marrow (BM) cells were decreased in comparison to WT mice. TET2(trap/trap) mice were born at an expected Mendelian frequency but died at a high rate by postnatal day 3, indicating TET2 to be essential for survival. In analysis of the hematopoietic system, transplantation of TET2(trap/trap), but not WT fetal liver cells, led to mild myeloid hyperplasia and splenomegaly in WT recipient mice, but no onsets of lethal hematological malignancies were observed during a follow-up period of 12 months. TET2 knockdown led to an increased serial replating capacity of BM cells in vitro and increased hematopoietic stem cell (HSC) self-renewal in vivo in competitive repopulation and serial transplantation assays. These data indicate that TET2 has a critical role in survival and HSC homeostasis.
authors.affiliation: Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shide
authors.forename: Takuro
authors.initials: T
authors.lastname: Kameda
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
mesh_terms: D000818:Animals; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D049308:Dioxygenases; D019337:Hematologic Neoplasms / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C551914:Tet2 protein, mouse