ELF5-enforced transcriptional networks define an epigenetically regulated trophoblast stem cell compartment in the human placenta
Abstract
The first definitive cell fate decision in development occurs at the blastocyst stage with establishment of the trophoblast and embryonic cell lineages. In the mouse, lineage commitment is achieved by epigenetic regulation of a critical gatekeeper gene, the transcription factor Elf5, that reinforces placental cell fate and is necessary for trophoblast stem (TS) cell self-renewal. In humans, however, the epigenetic lineage boundary seems to be less stringent since human embryonic stem (ES) cells, unlike their murine counterparts, harbour some potential to differentiate into trophoblast derivatives. Here, we show that ELF5 is expressed in the human placenta in villous cytotrophoblast cells but not in post-mitotic syncytiotrophoblast and invasive extravillous cytotrophoblast cells. ELF5 establishes a circuit of mutually interacting transcription factors with CDX2 and EOMES, and the highly proliferative ELF5(+)/CDX2(+) double-positive subset of cytotrophoblast cells demarcates a putative TS cell compartment in the early human placenta. In contrast to placental trophoblast, however, ELF5 is hypermethylated and largely repressed in human ES cells and derived trophoblast cell lines, as well as in induced pluripotent stem cells and murine epiblast stem cells. Thus, these cells exhibit an embryonic lineage-specific epigenetic signature and do not undergo an epigenetic reprogramming to reflect the trophoblast lineage at key loci such as ELF5. Our identification of the trophoblast-specific transcriptional circuit established by ELF5 will be instrumental to derive human TS cell lines that truly reflect early placental trophoblast and that will be most beneficial to gain insights into the aetiology of common pregnancy complications, including intra-uterine growth restriction and pre-eclampsia.
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The first trimester is a critical period for placental development, because expression of markers of trophoblast stemness declines rapidly after 12 weeks of gestation, suggesting loss of proliferative potential.
“The first trimester is a critical period for placental development, for expression of markers of trophoblast stemness decline rapidly after 12 weeks of gestation (252), suggesting loss of proliferative potential.”
From Placental Origins of Chronic Disease (2016) · cites this paper as [252]
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- Immunofluorescence localization of ELF5 to cytotrophoblasts in the human placenta. (A) Overview of 11 week placental villous cross-section shows ELF5 localization to nuclei of villous cytotrophoblasts, but absence from nuclei of the overlying syncytiotrophoblast layer. Cytotrophoblasts are a proliferative cell population that continuously divide to replenish the overlying syncytium. (B) Co-localization with cytokeratin 7 (CK7) confirms the trophoblast identity of ELF5-positive cells. (C) Confocal image of a double staining of ELF5 and the villous cytotrophoblast marker SPINT1 (also known as HAI-1) shows that every ELF5-positive nucleus resides within the cytotrophoblast layer. Top row 6 week, bottom row 11 week placenta. (D) Confocal image analysis of an 11 week villous section stained for ELF5 and the extravillous cytotrophoblast (EVT) marker integrin alpha-5 (ITGA5). ELF5 is detected only in nuclei at the proliferative base, but not further distal along the EVT column where cells adopt an invasive phenotype and lose proliferative potential. (E) ELF5 is also absent from post- mitotic interstitial and endovascular EVTs within the decidual bed. 2460 Human Molecular Genetics, 2010, Vol. 19, No. 12
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- Authors
- Hemberger, M., Udayashankar, R., Tesar, P., Moore, H., & Burton, G. J.
- Affiliations
- Babraham Institute (GB)
- University of Sheffield (GB)
- Case Western Reserve University (US)
- University of Cambridge (GB)
- Corresponding author
- Hemberger, Myriam
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-03-30
- Volume
- 19
- Issue
- 12
- Pages
- 2456-2467
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2134873562
- Cited by
- 181
- References
- 47
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 6 · 2023: 6 · 2022: 14 · 2021: 13 · 2020: 10 · 2019: 12 · 2018: 12 · 2017: 11 · 2016: 14 · 2015: 8 · 2014: 9 · 2013: 17 · 2012: 24
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- Biotechnology and Biological Sciences Research Council (BBS/E/B/0000C230)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- ELF5, trophoblast stem cells, human placenta, epigenetic regulation, transcriptional regulatory networks, CDX2, Eomes, cytotrophoblast, syncytiotrophoblast, extravillous cytotrophoblast, DNA methylation, human embryonic stem cells, induced pluripotent stem cells, epiblast stem cells, fetal growth restriction, preeclampsia
- MeSH terms
- CDX2 Transcription Factor, Animals, DNA-Binding Proteins, Female, Humans, Placenta, Pregnancy, Pregnancy Complications, Stem Cells, Transcription Factors, Trophoblasts, Homeodomain Proteins, Cell Lineage, DNA Methylation, Oligonucleotide Array Sequence Analysis, T-Box Domain Proteins, Pluripotent Stem Cells, Epigenesis, Genetic, Proto-Oncogene Proteins c-ets, Mice, Gene Regulatory Networks
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