title: An ex vivo model for imprinting: mutually exclusive binding of Cdx2 and Oct4 as a switch for imprinted and random X-inactivation.
abstract: In the early mammalian embryo, X chromosome inactivation (XCI) achieves dosage parity between males and females for X-linked genes. During mouse development, imprinted paternal XCI is observed first and switches to random XCI in the epiblast but not placental lineages. The mechanism by which this epigenetic switch occurs is currently unknown. Here, we establish an ex vivo model for imprinting and identify a novel trans-acting regulatory factor for imprinted XCI. Using an induced trophoblast stem cell (iTS) model, we show that embryonic stem (ES) cells transdifferentiated into trophoblasts retain partial memory of the XCI imprint. Cdx2, a stem cell factor that determines commitment to the extraembryonic lineage, directly binds Xist and activates expression of Xist RNA in extrembryonic cells. Cdx2 competes with Oct4, a stem cell factor that determines commitment to the embryonic lineage, for overlapping binding sites within Xist. We propose that mutually exclusive binding between Cdx2 and Oct4 in Xist underlies the switch between imprinted and random XCI in the early mouse embryo.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02214, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Erwin
authors.forename: Brian
authors.initials: B
authors.lastname: del Rosario
authors.forename: Bernhard
authors.initials: B
authors.lastname: Payer
authors.forename: Jeannie T
authors.initials: JT
authors.lastname: Lee
mesh_terms: D000483:Alleles; D000818:Animals; D000071616:CDX2 Transcription Factor; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D018392:Genomic Imprinting; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007438:Introns; D008297:Male; D051379:Mice; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes; D014327:Trophoblasts / Q000378:metabolism; D049951:X Chromosome Inactivation
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D062085:RNA, Long Noncoding; D014157:Transcription Factors; C077885:XIST non-coding RNA; C542956:Xite transcript, mouse