title: Early embryonic lethality of mice with disrupted transcription cofactor PIMT/NCOA6IP/Tgs1 gene.
abstract: PIMT (also known as PIPMT/NCOA6IP/Tgs1), first isolated as a transcription coactivator PRIP (NCOA6)-interacting 96-kDa protein with RNA-binding property, possesses RNA methyltransferase activity. As a transcription coactivator binding protein, PIMT enhances the nuclear receptor transcriptional activity and its methyltransferase property is involved in the formation of the 2,2,7-trimethylguanosine cap of non-coding small RNAs, but the in vivo functions of this gene have not been fully explored. To elucidate the biological functions, we used gene targeting to generate mice with a disrupted PIMT/Tgs1 gene. Disruption of PIMT gene results in early embryonic lethality due to impairment of development around the blastocyst and uterine implantation stages. We show that PIMT is expressed in all cells of the E3.5day blastocyst in the mouse. PIMT null mutation abolished PIMT expression in all cells of the blastocyst and caused a reduction in the expression of Oct4 and Nanog transcription factor proteins in the E3.5 blastocyst resulting in the near failure to form inner cell mass (ICM). With conditional deletion of PIMT gene, mouse embryonic fibroblasts (MEFs) exhibit defective wound healing in the scratch assay and a reduction in cell proliferation due to decreased G₀/G₁ transition and G₂/M phase cell cycle arrest. We conclude that PIMT/NCOA6IP, which is expressed in all cells of the 3.5 day stage blastocyst, is indispensable for early embryonic development.
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008, USA.
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Jia
authors.forename: Navin
authors.initials: N
authors.lastname: Viswakarma
authors.forename: Susan E
authors.initials: SE
authors.lastname: Crawford
authors.forename: Joy
authors.initials: J
authors.lastname: Sarkar
authors.forename: M
authors.initials: M
authors.lastname: Sambasiva Rao
authors.forename: William J
authors.initials: WJ
authors.lastname: Karpus
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Kanwar
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Zhu
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001755:Blastocyst / Q000378:metabolism*; D053624:Blastocyst Inner Cell Mass / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics; D049109:Cell Proliferation; D010064:Embryo Implantation / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014599:Uterus / Q000196:embryology* / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D014157:Transcription Factors; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase