EED and KDM6B Coordinate the First Mammalian Cell Lineage Commitment To Ensure Embryo Implantation

Saha, Biswarup; Home, Pratik; Ray, Soma; Larson, Melissa A.; Paul, Arindam; Rajendran, Ganeshkumar; Behr, Barry

doi:10.1128/mcb.00069-13

Cited by 53 publications

(56 citation statements)

References 60 publications

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“…The regulation of Cdx2 expression in early embryos and other developmental contexts is mediated by transcriptional and epigenetic mechanisms (Chen et al, 2009;Home et al, 2009Home et al, , 2012Yeap et al, 2009;Yuan et al, 2009;Saha et al, 2013;Rayon et al, 2014). Several key regulatory regions are present in Cdx2 (Wang and Shashikant, 2007;Benahmed et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor AP-2γ induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage

et al. 2015

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Cell fate decisions are fundamental to the development of multicellular organisms. In mammals the first cell fate decision involves segregation of the pluripotent inner cell mass and the trophectoderm, a process regulated by cell polarity proteins, HIPPO signaling and lineagespecific transcription factors such as CDX2. However, the regulatory mechanisms that operate upstream to specify the trophectoderm lineage have not been established. Here we report that transcription factor AP-2γ (TFAP2C) functions as a novel upstream regulator of Cdx2 expression and position-dependent HIPPO signaling in mice. Loss-and gain-of-function studies and promoter analysis revealed that TFAP2C binding to an intronic enhancer is required for activation of Cdx2 expression during early development. During the 8-cell to morula transition TFAP2C potentiates cell polarity to suppress HIPPO signaling in the outside blastomeres. TFAP2C depletion triggered downregulation of PARD6B, loss of apical cell polarity, disorganization of F-actin, and activation of HIPPO signaling in the outside blastomeres. Rescue experiments using Pard6b mRNA restored cell polarity but only partially corrected position-dependent HIPPO signaling, suggesting that TFAP2C negatively regulates HIPPO signaling via multiple pathways. Several genes involved in regulation of the actin cytoskeleton (including Rock1, Rock2) were downregulated in TFAP2C-depleted embryos. Inhibition of ROCK1 and ROCK2 activity during the 8-cell to morula transition phenocopied TFAP2C knockdown, triggering a loss of position-dependent HIPPO signaling and decrease in Cdx2 expression. Altogether, these results demonstrate that TFAP2C facilitates trophectoderm lineage specification by functioning as a key regulator of Cdx2 transcription, cell polarity and position-dependent HIPPO signaling.

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Section: Discussionmentioning

confidence: 99%

Transcription factor AP-2γ induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage

et al. 2015

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“…H3K27Me3 is another histone modification implicated in transcriptional repression of TE-specific genes within the ICM lineage cells (Saha, et al 2013). H3K27Me3 modification is regulated by polycomb repressor 2 (PRC2) complex.…”

Section: Histone Modifications and Trophoblast Developmentmentioning

confidence: 99%

“…Recently, it was reported that proper regulation of H3K27Me3 incorporation at TE-specific genes is important during preimplantation lineage development. Loss of H3K27Me3 incorporation at the TE-specific genes like Cdx2 and Gata3 is essential for proper development of the TE lineage and embryo implantation (Saha, et al 2013). Analyses in mouse embryos indicated that coordinated regulation of lysine-specific histone demethylase 6B and embryonic ectoderm development (EED), a core component of PRC2, ensures loss of He3K27Me3 incorporation at the chromatin domains of TE/TSC-specific genes (Rugg-Gunn, et al 2010, Saha, et al 2013).…”

Section: Histone Modifications and Trophoblast Developmentmentioning

confidence: 99%

“…Loss of H3K27Me3 incorporation at the TE-specific genes like Cdx2 and Gata3 is essential for proper development of the TE lineage and embryo implantation (Saha, et al 2013). Analyses in mouse embryos indicated that coordinated regulation of lysine-specific histone demethylase 6B and embryonic ectoderm development (EED), a core component of PRC2, ensures loss of He3K27Me3 incorporation at the chromatin domains of TE/TSC-specific genes (Rugg-Gunn, et al 2010, Saha, et al 2013). Although loss of H3K27Me3 modification promotes TE-specific gene expression, incorporation of H3K27Me3 may be important for proper development and differentiation of trophoblast progenitors.…”

Section: Histone Modifications and Trophoblast Developmentmentioning

confidence: 99%

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Transcriptional regulators of the trophoblast lineage in mammals with hemochorial placentation

Knott¹,

Paul²

2014

Reproduction

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Mammalian reproduction is critically dependent on the trophoblast cell lineage, which assures proper establishment of maternal-fetal interactions during pregnancy. Specification of trophoblast cell lineage begins with the development of the trophectoderm (TE) in preimplantation embryos. Subsequently, other trophoblast cell types arise with progression of pregnancy. Studies with transgenic animal models as well as trophoblast stem/progenitor cells have implicated distinct transcriptional and epigenetic regulators in trophoblast lineage development. This review focuses on our current understanding of transcriptional and epigenetic mechanisms regulating specification, determination, maintenance and differentiation of trophoblast cells.

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“…In conjunction with the HIPPO pathway, OCT4 and CDX2 negatively regulate one another's expression in the ICM and trophoblast lineages via binding to each other's promoters and cooperating with ERG-associated protein with SET domain (ESET) and BRG1 (Brahma-related gene 1), a chromatin-remodeling protein, to block transcription (13)(14)(15). Other epigenetic modifiers, such as embryonic ectoderm development (EED) and lysine (K)-specific demethylase 6B (KDM6B), work in opposition to restrict Cdx2 and Gata3 expression to the trophoblast lineage (16). Altogether, these studies demonstrate that ICM and trophoblast lineage development is regulated by overlapping transcriptional and epigenetic mechanisms.…”

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confidence: 99%

BRG1 Governs Nanog Transcription in Early Mouse Embryos and Embryonic Stem Cells via Antagonism of Histone H3 Lysine 9/14 Acetylation

Carey

Cao

Choi

et al. 2015

Molecular and Cellular Biology

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c During mouse preimplantation development, the generation of the inner cell mass (ICM) and trophoblast lineages comprises upregulation of Nanog expression in the ICM and its silencing in the trophoblast. However, the underlying epigenetic mechanisms that differentially regulate Nanog in the first cell lineages are poorly understood. Here, we report that BRG1 (Brahmarelated gene 1) cooperates with histone deacetylase 1 (HDAC1) to regulate Nanog expression. BRG1 depletion in preimplantation embryos and Cdx2-inducible embryonic stem cells (ESCs) revealed that BRG1 is necessary for Nanog silencing in the trophoblast lineage. Conversely, in undifferentiated ESCs, loss of BRG1 augmented Nanog expression. Analysis of histone H3 within the Nanog proximal enhancer revealed that H3 lysine 9/14 (H3K9/14) acetylation increased in BRG1-depleted embryos and ESCs. Biochemical studies demonstrated that HDAC1 was present in BRG1-BAF155 complexes and BRG1-HDAC1 interactions were enriched in the trophoblast lineage. HDAC1 inhibition triggered an increase in H3K9/14 acetylation and a corresponding rise in Nanog mRNA and protein, phenocopying BRG1 knockdown embryos and ESCs. Lastly, nucleosome-mapping experiments revealed that BRG1 is indispensable for nucleosome remodeling at the Nanog enhancer during trophoblast development. In summary, our data suggest that BRG1 governs Nanog expression via a dual mechanism involving histone deacetylation and nucleosome remodeling. C ell fate decisions are crucial for the development of multicellular organisms. In higher animals, such as placental mammals, the first cell fate decision occurs during preimplantation development, when the totipotent blastomeres differentiate into the blastocyst inner cell mass (ICM) and trophoblast lineages (1). The proper development of the blastocyst ICM and trophoblast lineages is critical for embryo implantation, placentation, gastrulation, and full-term development. Abnormal development of the ICM and trophoblast lineages may contribute to pregnancy loss, reproductive disorders, and birth defects.Early lineage formation in preimplantation embryos is mediated by a combination of transcriptional and epigenetic mechanisms (2, 3). During blastocyst formation, the expression of key transcription factors, such as octamer-binding transcription factor 4 (OCT4), Nanog homeobox (NANOG), and sex-determining region Y box 2 (SOX2), becomes restricted to the pluripotent ICM, while transcription factor AP-2 gamma (TFAP2C), GATA binding protein 3 (GATA3), and caudal type homeobox 2 (CDX2) are expressed exclusively in the trophoblast lineage (4-10). The spatial and temporal expression of these lineage-specific factors is controlled by position-dependent HIPPO signaling, transcription factor regulatory loops, and chromatin modifications (2,3,(10)(11)(12). For example, the HIPPO signaling pathway differentially regulates lineage formation via the downregulation of CDX2 expression in the ICM and SOX2 expression in the trophoblast (10, 12). In conjunction with the HIPPO pathway, O...

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EED and KDM6B Coordinate the First Mammalian Cell Lineage Commitment To Ensure Embryo Implantation

Cited by 53 publications

References 60 publications

Transcription factor AP-2γ induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage

Transcription factor AP-2γ induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage

Transcriptional regulators of the trophoblast lineage in mammals with hemochorial placentation

BRG1 Governs Nanog Transcription in Early Mouse Embryos and Embryonic Stem Cells via Antagonism of Histone H3 Lysine 9/14 Acetylation

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