An ex vivo model for imprinting: mutually exclusive binding of Cdx2 and Oct4 as a switch for imprinted and random X-inactivation

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 ep...

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Bibliographic Details
Published in:Genetics (Austin) 2012-11, Vol.192 (3), p.857-868
Main Authors: Erwin, Jennifer A, del Rosario, Brian, Payer, Bernhard, Lee, Jeannie T
Format: Article
Language:English
Subjects:
Alleles
Animals
CDX2 Transcription Factor
Chromosomes
Embryonic Stem Cells - metabolism
Embryos
Epigenetics
Female
Gene expression
Genomic Imprinting
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Introns
Investigations
Male
Mammals
Mice
Octamer Transcription Factor-3 - genetics
Octamer Transcription Factor-3 - metabolism
Protein Binding
RNA, Long Noncoding - metabolism
Transcription Factors - genetics
Transcription Factors - metabolism
Transgenes
Trophoblasts - metabolism
X Chromosome Inactivation
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Summary: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.
ISSN:1943-2631
0016-6731
1943-2631
DOI:10.1534/genetics.112.144121