title: Impaired placental trophoblast lineage differentiation in Alkbh1(-/-) mice.
abstract: E. coli AlkB has been intensively studied since 1983, but the in vivo roles of its mammalian homologue Alkbh1 are unknown. We, therefore, created null mice for Alkbh1. Alkbh1 mRNA is expressed at highest levels in the trophoblast lineages of the developing placenta. Alkbh1(-/-) placentas have decreased expression of differentiated trophoblast markers including Tpbp, Gcm1, and Pl-1, and increased expression of the trophoblast stem cell marker Eomes. Alkbh1 localizes to nuclear euchromatin, and interacts strongly with Mrj, an essential placental gene that mediates gene repression by recruitment of class II histone deacetylases (HDACs). Competition experiments show Alkbh1 and HDAC4 binding to Mrj are mutually exclusive, which causes decreased HDAC activity and increased target gene expression. Our study demonstrates Alkbh1 performs important functions in placental trophoblast lineage differentiation and participates in mechanisms of transcriptional regulation.
authors.affiliation: Department of Medicine, University of California, Irvine, Irvine, California 92697, USA.
authors.forename: Zishu
authors.initials: Z
authors.lastname: Pan
authors.forename: Shaheen
authors.initials: S
authors.lastname: Sikandar
authors.forename: Mavee
authors.initials: M
authors.lastname: Witherspoon
authors.forename: Diana
authors.initials: D
authors.lastname: Dizon
authors.forename: Terrence
authors.initials: T
authors.lastname: Nguyen
authors.forename: Kurt
authors.initials: K
authors.lastname: Benirschke
authors.forename: Christopher
authors.initials: C
authors.lastname: Wiley
authors.forename: Paul
authors.initials: P
authors.lastname: Vrana
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
mesh_terms: D000071498:AlkB Homolog 1, Histone H2a Dioxygenase; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D016000:Cluster Analysis; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D049308:Dioxygenases / Q000235:genetics*; D022041:Euchromatin / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D018832:Molecular Chaperones / Q000378:metabolism; D010802:Phylogeny; D010920:Placenta / Q000166:cytology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014327:Trophoblasts / Q000502:physiology*; D020798:Two-Hybrid System Techniques
chemical_list: C118476:Dnajb6 protein, mouse; D022041:Euchromatin; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D014157:Transcription Factors; D049308:Dioxygenases; D000071498:AlkB Homolog 1, Histone H2a Dioxygenase; C529511:Alkbh1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase