title: Arid3a is essential to execution of the first cell fate decision via direct embryonic and extraembryonic transcriptional regulation.
abstract: Despite their origin from the inner cell mass, embryonic stem (ES) cells undergo differentiation to the trophectoderm (TE) lineage by repression of the ES cell master regulator Oct4 or activation of the TE master regulator Caudal-type homeobox 2 (Cdx2). In contrast to the in-depth studies of ES cell self-renewal and pluripotency, few TE-specific regulators have been identified, thereby limiting our understanding of mechanisms underlying the first cell fate decision. Here we show that up-regulation and nuclear entry of AT-rich interactive domain 3a (Arid3a) drives TE-like transcriptional programs in ES cells, maintains trophoblast stem (TS) cell self-renewal, and promotes further trophoblastic differentiation both upstream and independent of Cdx2. Accordingly, Arid3a(-/-) mouse post-implantation placental development is severely impaired, resulting in early embryonic death. We provide evidence that Arid3a directly activates TE-specific and trophoblast lineage-specific genes while directly repressing pluripotency genes via differential regulation of epigenetic acetylation or deacetylation. Our results identify Arid3a as a critical regulator of TE and placental development through execution of the commitment and differentiation phases of the first cell fate decision.
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rhee
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology.
authors.forename: Bum-Kyu
authors.initials: BK
authors.lastname: Lee
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology.
authors.forename: Samuel
authors.initials: S
authors.lastname: Beck
authors.affiliation: Department of Molecular Biosciences.
authors.forename: Azeen
authors.initials: A
authors.lastname: Anjum
authors.affiliation: Department of Molecular Biosciences.
authors.forename: Kendra R
authors.initials: KR
authors.lastname: Cook
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology.
authors.forename: Melissa
authors.initials: M
authors.lastname: Popowski
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, jonghwankim@mail.utexas.edu haleytucker@austin.utexas.edu.
authors.forename: Haley O
authors.initials: HO
authors.lastname: Tucker
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, Center for Systems and Synthetic Biology, The University of Texas at Austin, Austin, Texas 78712, USA jonghwankim@mail.utexas.edu haleytucker@austin.utexas.edu.
authors.forename: Jonghwan
authors.initials: J
authors.lastname: Kim
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010929:Placentation; D011247:Pregnancy; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C097532:Arid3a protein, mouse; D004268:DNA-Binding Proteins; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D014157:Transcription Factors
keywords: Arid3a; embryonic stem cells; first cell fate decision; trans-differentiation; trophectoderm; trophoblast stem cells