Impaired placental trophoblast lineage differentiation in Alkbh1(-/-) mice.
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.
Pan
Zishu
Z
Department of Medicine, University of California, Irvine, Irvine, California 92697, USA.
Sikandar
Shaheen
S
Witherspoon
Mavee
M
Dizon
Diana
D
Nguyen
Terrence
T
Benirschke
Kurt
K
Wiley
Christopher
C
Vrana
Paul
P
Lipkin
Steven M
SM
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
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