Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5

Ng, Ray Kit; Dean, Wendy; Dawson, Claire; Lucifero, Diana; Madeja, Zofia E.; Reik, Wolf; Hemberger, Myriam

doi:10.1038/ncb1786

Cited by 322 publications

(362 citation statements)

References 44 publications

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“…Despite the mutual coactivation capacity of the three core TSC TFs Cdx2, Eomes, and Elf5, previous evidence showed that their expression patterns do not fully overlap (Ng et al 2008). In outgrowths of trophoblast tissue, it was observed that the central, most TSC-like cells are largely double positive for Cdx2 and Elf5, while the surrounding, flatter cells still retain Elf5 but have largely lost Cdx2 (Supplemental Fig.…”

Section: Elf5 Levels Are Critical For the Establishment Of A Prolifermentioning

confidence: 95%

“…However, despite coexpression in the TSC compartment in vivo and in vitro, the precise temporal and spatial expression domains of these various TFs are not fully overlapping. For instance, Cdx2 and Elf5 are coexpressed in TSCs, but, upon induction of differentiation, Cdx2 is down-regulated more rapidly than Elf5 (Ng et al 2008). Similarly in vivo, Cdx2 and Eomes are restricted to a narrow region of the ExE immediately overlying the epiblast, whereas Elf5 and Tfap2c have a much broader expression domain extending into the proximal ExE and ectoplacental cone (EPC) (Auman et al 2002;Ng et al 2008;Ralston and Rossant 2008;Kuckenberg et al 2010;Adachi et al 2013).…”

mentioning

confidence: 99%

“…For instance, Cdx2 and Elf5 are coexpressed in TSCs, but, upon induction of differentiation, Cdx2 is down-regulated more rapidly than Elf5 (Ng et al 2008). Similarly in vivo, Cdx2 and Eomes are restricted to a narrow region of the ExE immediately overlying the epiblast, whereas Elf5 and Tfap2c have a much broader expression domain extending into the proximal ExE and ectoplacental cone (EPC) (Auman et al 2002;Ng et al 2008;Ralston and Rossant 2008;Kuckenberg et al 2010;Adachi et al 2013). These data point to a seeming discrepancy: Although core TFs are coexpressed and can mutually activate each other in the TSC compartment, their expression domains become divergent with the onset of differentiation.…”

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confidence: 99%

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Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks

et al. 2015

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Elf5 is a transcription factor with pivotal roles in the trophoblast compartment, where it reinforces a trophoblast stem cell (TSC)-specific transcriptional circuit. However, Elf5 is also present in differentiating trophoblast cells that have ceased to express other TSC genes such as Cdx2 and Eomes. In the present study, we aimed to elucidate the context-dependent role of Elf5 at the interface between TSC self-renewal and the onset of differentiation. We demonstrate that precise levels of Elf5 are critical for normal expansion of the TSC compartment and embryonic survival, as Elf5 overexpression triggers precocious trophoblast differentiation. Through integration of protein interactome, transcriptome, and genome-wide chromatin immunoprecipitation data, we reveal that this abundancedependent function is mediated through a shift in preferred Elf5-binding partners; in TSCs, Elf5 interaction with Eomes recruits Tfap2c to triply occupied sites at TSC-specific genes, driving their expression. In contrast, the Elf5 and Tfap2c interaction becomes predominant as their protein levels increase. This triggers binding to double-and single-occupancy sites that harbor the cognate Tfap2c motif, causing activation of the associated differentiationpromoting genes. These data place Elf5 at the center of a stoichiometry-sensitive transcriptional network, where it acts as a molecular switch governing the balance between TSC proliferation and differentiation.

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Section: Elf5 Levels Are Critical For the Establishment Of A Prolifermentioning

confidence: 95%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks

et al. 2015

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“…Results from such studies have led to identification of Cdx2 (caudal type homeobox 2), a member of the caudal-related homeobox transcription factor gene family, the expression of which has been shown to be required for maintenance of TE and TSCs in the mouse embryo (6, 7). Other transcription factors, including Elf5 (Ets domain transcription factor) and Eomes (Eomesodermin), also have been shown to be required for maintenance of the TSC fate in the mouse (8,9).…”

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confidence: 99%

Human pluripotent stem cells as a model of trophoblast differentiation in both normal development and disease

Horii

Wakeland

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

132

164

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Trophoblast is the primary epithelial cell type in the placenta, a transient organ required for proper fetal growth and development. Different trophoblast subtypes are responsible for gas/nutrient exchange (syncytiotrophoblasts, STBs) and invasion and maternal vascular remodeling (extravillous trophoblasts, EVTs). Studies of early human placental development are severely hampered by the lack of a representative trophoblast stem cell (TSC) model with the capacity for self-renewal and the ability to differentiate into both STBs and EVTs. Primary cytotrophoblasts (CTBs) isolated from early-gestation (6-8 wk) human placentas are bipotential, a phenotype that is lost with increasing gestational age. We have identified a CDX2 + /p63 + CTB subpopulation in the early postimplantation human placenta that is significantly reduced later in gestation. We describe a reproducible protocol, using defined medium containing bone morphogenetic protein 4 by which human pluripotent stem cells (hPSCs) can be differentiated into CDX2 + /p63 + CTB stem-like cells. These cells can be replated and further differentiated into STB-and EVT-like cells, based on marker expression, hormone secretion, and invasive ability. As in primary CTBs, differentiation of hPSC-derived CTBs in low oxygen leads to reduced human chorionic gonadotropin secretion and STB-associated gene expression, instead promoting differentiation into HLA-G + EVTs in an hypoxiainducible, factor-dependent manner. To validate further the utility of hPSC-derived CTBs, we demonstrated that differentiation of trisomy 21 (T21) hPSCs recapitulates the delayed CTB maturation and blunted STB differentiation seen in T21 placentae. Collectively, our data suggest that hPSCs are a valuable model of human placental development, enabling us to recapitulate processes that result in both normal and diseased pregnancies.human pluripotent stem cells | cytotrophoblast | extravillous trophoblast | syncytiotrophoblast | placenta

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“…How genetic factors and epigenetic modifiers interact to regulate lineage decisions is therefore an important goal among stem cell researchers and developmental biologists alike. Targeted deletion of numerous epigenetic modifiers has been shown to result in ectopic expression of lineage-specific genes and periimplantation lethality, demonstrating that establishment and maintenance of an epigenetic program is essential for the earliest stages of development (3)(4)(5).…”

mentioning

confidence: 99%

Distinct histone modifications in stem cell lines and tissue lineages from the early mouse embryo

Rugg‐Gunn

Cox

Ralston

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

207

199

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A unique property of the mammalian embryo is that stem cells can be derived from its early tissue lineages. These lineages will give rise to the fetus as well as essential extraembryonic tissues. Understanding how chromatin regulation participates in establishment of these lineages in the embryo and their derived stem cells provides insight that will critically inform our understanding of embryogenesis and stem cell biology. Here, we compare the genomewide location of active and repressive histone modifications in embryonic stem cells, trophoblast stem cells, and extraembryonic endoderm stem cells from the mouse. Our results show that the active modification H3K4me3 has a similar role in the three stem cell types, but the repressive modification H3K27me3 varies in abundance and genomewide distribution. Thus, alternative mechanisms mediate transcriptional repression in stem cells from the embryo. In addition, using carrier chromatin immunoprecipitation we show that bivalent histone domains seen in embryonic stem cells exist in pluripotent cells of the early embryo. However, the epigenetic status of extraembryonic progenitor cells in the embryo did not entirely reflect the extraembryonic stem cell lines. These studies indicate that histone modification mechanisms may differ between early embryo lineages and emphasize the importance of examining in vivo and in vitro progenitor cells.epigenetics | methylation | embryogenesis | extraembryonic

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Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5

Cited by 322 publications

References 44 publications

Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks

Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks

Human pluripotent stem cells as a model of trophoblast differentiation in both normal development and disease

Distinct histone modifications in stem cell lines and tissue lineages from the early mouse embryo

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