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Mechanisms of early placental development in mouse and humans

Nature Reviews Genetics volume 21, pages 27–43 (2020)Cite this article

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Abstract

The importance of the placenta in supporting mammalian development has long been recognized, but our knowledge of the molecular, genetic and epigenetic requirements that underpin normal placentation has remained remarkably under-appreciated. Both the in vivo mouse model and in vitro-derived murine trophoblast stem cells have been invaluable research tools for gaining insights into these aspects of placental development and function, with recent studies starting to reshape our view of how a unique epigenetic environment contributes to trophoblast differentiation and placenta formation. These advances, together with recent successes in deriving human trophoblast stem cells, open up new and exciting prospects in basic and clinical settings that will help deepen our understanding of placental development and associated disorders of pregnancy.

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Fig. 1: Key stages of mouse and human placental development.
Fig. 2: Transcriptional networks in trophoblast stem cells.
Fig. 3: Distinct epigenetic dynamics and features of the first cell lineages in mice.
Fig. 4: The placenta affects the development of particular embryonic organ systems.
Fig. 5: Novel in vitro tools for studying early mammalian development.

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References

  1. Brosens, I., Pijnenborg, R., Vercruysse, L. & Romero, R. The “Great Obstetrical Syndromes” are associated with disorders of deep placentation. Am. J. Obstet. Gynecol. 204, 193–201 (2011).

    Article  PubMed  Google Scholar 

  2. Pijnenborg, R., Robertson, W. B., Brosens, I. & Dixon, G. Trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals. Placenta 2, 71–91 (1981).

    Article  CAS  PubMed  Google Scholar 

  3. Napso, T., Yong, H. E. J., Lopez-Tello, J. & Sferruzzi-Perri, A. N. The role of placental hormones in mediating maternal adaptations to support pregnancy and lactation. Front. Physiol. 9, 1091 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  4. PrabhuDas, M. et al. Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nat. Immunol. 16, 328–334 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Moffett, A. & Loke, C. Immunology of placentation in eutherian mammals. Nat. Rev. Immunol. 6, 584–594 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Tanaka, S., Kunath, T., Hadjantonakis, A. K., Nagy, A. & Rossant, J. Promotion of trophoblast stem cell proliferation by FGF4. Science 282, 2072–2075 (1998). This study describes the ground-breaking derivation of mouse trophoblast stem cells, thereby providing a fundamental research tool that has substantially advanced our understanding of the mechanistic principles underlying trophoblast development.

    Article  CAS  PubMed  Google Scholar 

  7. Gamage, T. K., Chamley, L. W. & James, J. L. Stem cell insights into human trophoblast lineage differentiation. Hum. Reprod. Update 23, 77–103 (2016).

    Article  PubMed  CAS  Google Scholar 

  8. Cambuli, F. et al. Epigenetic memory of the first cell fate decision prevents complete ES cell reprogramming into trophoblast. Nat. Commun. 5, 5538 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Malassine, A., Frendo, J. L. & Evain-Brion, D. A comparison of placental development and endocrine functions between the human and mouse model. Hum. Reprod. Update 9, 531–539 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Okae, H. et al. Derivation of human trophoblast stem cells. Cell Stem Cell 22, 50–63.e56 (2018). More than 20 years after the generation of trophoblast stem cells in the mouse, this paper is one of three published in 2018 that describe the derivation of human trophoblast stem cells in vitro, paving the way to define the transcription factor networks and mechanistic principles governing human early placental development.

    Article  CAS  PubMed  Google Scholar 

  11. Haider, S. et al. Self-renewing trophoblast organoids recapitulate the developmental program of the early human placenta. Stem Cell Rep. 11, 537–551 (2018). The second of three papers published in 2018 that describe the isolation and perpetuation of human trophoblast stem cells directly from early first-trimester placenta, here using organoid culture approaches.

    Article  CAS  Google Scholar 

  12. Turco, M. Y. et al. Trophoblast organoids as a model for maternal-fetal interactions during human placentation. Nature 564, 263–267 (2018). Building on an earlier study by the same group that had generated human endometrial glandular organoids, this is the third of the three papers published in 2018 to describe the derivation of human trophoblast stem cells, in this case through the use of 3D organoid culture systems.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ramathal, C. Y., Bagchi, I. C., Taylor, R. N. & Bagchi, M. K. Endometrial decidualization: of mice and men. Semin. Reprod. Med. 28, 17–26 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Knofler, M. Critical growth factors and signalling pathways controlling human trophoblast invasion. Int. J. Dev. Biol. 54, 269–280 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Moffett, A. & Colucci, F. Uterine NK cells: active regulators at the maternal-fetal interface. J. Clin. Invest. 124, 1872–1879 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Woods, L. et al. Decidualisation and placentation defects are a major cause of age-related reproductive decline. Nat. Commun. 8, 352 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Klemmt, P. A., Carver, J. G., Kennedy, S. H., Koninckx, P. R. & Mardon, H. J. Stromal cells from endometriotic lesions and endometrium from women with endometriosis have reduced decidualization capacity. Fertil. Steril. 85, 564–572 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Copp, A. J. Death before birth: clues from gene knockouts and mutations. Trends Genet. 11, 87–93 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Perez-Garcia, V. et al. Placentation defects are highly prevalent in embryonic lethal mouse mutants. Nature 555, 463–468 (2018). This paper describes a comprehensive analysis of placental phenotypes in mouse gene knockouts that cause embryonic lethality, showing that placental development is very frequently affected in these mutants.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ueno, M. et al. c-Met-dependent multipotent labyrinth trophoblast progenitors establish placental exchange interface. Dev. Cell 27, 373–386 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Natale, B. V. et al. Sca-1 identifies a trophoblast population with multipotent potential in the mid-gestation mouse placenta. Sci. Rep. 7, 5575 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. James, J. L., Carter, A. M. & Chamley, L. W. Human placentation from nidation to 5 weeks of gestation. Part I: what do we know about formative placental development following implantation? Placenta 33, 327–334 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Knöfler, M. et al. Human placenta and trophoblast development: key molecular mechanisms and model systems. Cell. Mol. Life Sci. https://doi.org/10.1007/s00018-019-03104-6 (2019). This outstanding, comprehensive review of human placental development focuses on stem cells and their use in understanding trophoblast lineage specification and commitment and is accompanied by instructive diagrams and transcription factor hierarchies.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Boyd, J. D. & Hamilton, W. J. The Human Placenta (Heffer & Sons, 1970).

  25. Burton, G. J., Jauniaux, E. & Watson, A. L. Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd collection revisited. Am. J. Obstet. Gynecol. 181, 718–724 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Burton, G. J., Watson, A. L., Hempstock, J., Skepper, J. N. & Jauniaux, E. Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. J. Clin. Endocrinol. Metab. 87, 2954–2959 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Rossant, J. & Cross, J. C. Placental development: lessons from mouse mutants. Nat. Rev. Genet. 2, 538–548 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Woods, L., Perez-Garcia, V. & Hemberger, M. Regulation of placental development and its impact on fetal growth-new insights from mouse models. Front. Endocrinol. 9, 570 (2018).

    Article  Google Scholar 

  29. Adamson, S. L. et al. Interactions between trophoblast cells and the maternal and fetal circulation in the mouse placenta. Dev. Biol. 250, 358–373 (2002). This seminal study on the architecture of the mouse placental vasculature outlines the anatomy of maternal blood spaces and the nature of maternal–fetal vascular interactions, matching structure to function.

    Article  CAS  PubMed  Google Scholar 

  30. Niwa, H. et al. Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 123, 917–929 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Arnold, S. J. & Robertson, E. J. Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nat. Rev. Mol. Cell Biol. 10, 91–103 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Dietrich, J. E. & Hiiragi, T. Stochastic patterning in the mouse pre-implantation embryo. Development 134, 4219–4231 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Strumpf, D. et al. Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Development 132, 2093–2102 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Nishioka, N. et al. Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos. Mech. Dev. 125, 270–283 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Nishioka, N. et al. The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev. Cell 16, 398–410 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Blakeley, P. et al. Defining the three cell lineages of the human blastocyst by single-cell RNA-seq. Development 142, 3151–3165 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Horii, M. et al. Human pluripotent stem cells as a model of trophoblast differentiation in both normal development and disease. Proc. Natl Acad. Sci. USA 113, E3882–E3891 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Soncin, F. et al. Comparative analysis of mouse and human placentae across gestation reveals species-specific regulators of placental development. Development 145, dev156273 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Hemberger, M., Udayashankar, R., Tesar, P., Moore, H. & Burton, G. J. ELF5-enforced transcriptional networks define an epigenetically regulated trophoblast stem cell compartment in the human placenta. Hum. Mol. Genet. 19, 2456–2467 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Home, P. et al. Altered subcellular localization of transcription factor TEAD4 regulates first mammalian cell lineage commitment. Proc. Natl Acad. Sci. USA 109, 7362–7367 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yagi, R. et al. Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development. Development 134, 3827–3836 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Kidder, B. L. & Palmer, S. Examination of transcriptional networks reveals an important role for TCFAP2C, SMARCA4, and EOMES in trophoblast stem cell maintenance. Genome Res. 20, 458–472 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Latos, P. A. & Hemberger, M. The transcriptional and signalling networks of mouse trophoblast stem cells. Placenta 35, S81–S85 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Russ, A. P. et al. Eomesodermin is required for mouse trophoblast development and mesoderm formation. Nature 404, 95–99 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Donnison, M. et al. Loss of the extraembryonic ectoderm in Elf5 mutants leads to defects in embryonic patterning. Development 132, 2299–2308 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Yamamoto, H. et al. Defective trophoblast function in mice with a targeted mutation of Ets2. Genes Dev. 12, 1315–1326 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wen, F. et al. Ets2 is required for trophoblast stem cell self-renewal. Dev. Biol. 312, 284–299 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Luo, J. et al. Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-beta. Nature 388, 778–782 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Adachi, K. et al. Context-dependent wiring of Sox2 regulatory networks for self-renewal of embryonic and trophoblast stem cells. Mol. Cell 52, 380–392 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Latos, P. A. et al. Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells. Nat. Commun. 6, 7776 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Knott, J. G. & Paul, S. Transcriptional regulators of the trophoblast lineage in mammals with hemochorial placentation. Reproduction 148, R121–R136 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Ralston, A. et al. Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2. Development 137, 395–403 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Home, P. et al. GATA3 is selectively expressed in the trophectoderm of peri-implantation embryo and directly regulates Cdx2 gene expression. J. Biol. Chem. 284, 28729–28737 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Avilion, A. A. et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 17, 126–140 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kuckenberg, P. et al. The transcription factor TCFAP2C/AP-2gamma cooperates with CDX2 to maintain trophectoderm formation. Mol. Cell. Biol. 30, 3310–3320 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kunath, T. et al. Developmental differences in the expression of FGF receptors between human and mouse embryos. Placenta 35, 1079–1088 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Lee, C. Q. et al. What is trophoblast? a combination of criteria define human first-trimester trophoblast. Stem Cell Rep. 6, 257–272 (2016).

    Article  CAS  Google Scholar 

  58. Lee, Y. et al. A unifying concept of trophoblastic differentiation and malignancy defined by biomarker expression. Hum. Pathol. 38, 1003–1013 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Niwa, H., Miyazaki, J. & Smith, A. G. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat. Genet. 24, 372–376 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Latos, P. A. et al. Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks. Genes Dev. 29, 2435–2448 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hu, S. et al. DNA methylation presents distinct binding sites for human transcription factors. eLife 2, e00726 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Yin, Y. et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 356, eaaj2239 (2017). This paper systematically analyses the DNA-binding preferences of human transcription factors that depend on the methylation state of CpGs contained within their cognate motifs, thus directly linking the transcription factor network with the epigenome to explain cell fate specification and cellular commitment decisions.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Hartl, D. et al. CG dinucleotides enhance promoter activity independent of DNA methylation. Genome Res. 29, 554–563 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bourque, G. et al. Evolution of the mammalian transcription factor binding repertoire via transposable elements. Genome Res. 18, 1752–1762 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Pavlicev, M., Hiratsuka, K., Swaggart, K. A., Dunn, C. & Muglia, L. Detecting endogenous retrovirus-driven tissue-specific gene transcription. Genome Biol. Evol. 7, 1082–1097 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Walsh, C. P., Chaillet, J. R. & Bestor, T. H. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat. Genet. 20, 116–117 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Bestor, T. H. & Bourc'his, D. Transposon silencing and imprint establishment in mammalian germ cells. Cold Spring Harb. Symp. Quant. Biol. 69, 381–387 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Lavie, L., Kitova, M., Maldener, E., Meese, E. & Mayer, J. CpG methylation directly regulates transcriptional activity of the human endogenous retrovirus family HERV-K(HML-2). J. Virol. 79, 876–883 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Macfarlan, T. S. et al. Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A. Genes Dev. 25, 594–607 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Cohen, C. J. et al. Placenta-specific expression of the interleukin-2 (IL-2) receptor beta subunit from an endogenous retroviral promoter. J. Biol. Chem. 286, 35543–35552 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chuong, E. B., Rumi, M. A., Soares, M. J. & Baker, J. C. Endogenous retroviruses function as species-specific enhancer elements in the placenta. Nat. Genet. 45, 325–329 (2013). This study identifies endogenous retrovirus-derived LTR elements that serve important functions as trophoblast transcription factor binding sites in mammalian evolution.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Macfarlan, T. S. et al. Embryonic stem cell potency fluctuates with endogenous retrovirus activity. Nature 487, 57–63 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Brind'Amour, J. et al. LTR retrotransposons transcribed in oocytes drive species-specific and heritable changes in DNA methylation. Nat. Commun. 9, 3331 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Dunn-Fletcher, C. E. et al. Anthropoid primate-specific retroviral element THE1B controls expression of CRH in placenta and alters gestation length. PLOS Biol. 16, e2006337 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Huh, J. W., Ha, H. S., Kim, D. S. & Kim, H. S. Placenta-restricted expression of LTR-derived NOS3. Placenta 29, 602–608 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Mi, S. et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403, 785–789 (2000). This paper describes the remarkable situation in which a human endogenous retrovirus-derived gene, HERV-W, has been sequestered to serve an important physiological function in placental syncytiotrophoblast formation.

    Article  CAS  PubMed  Google Scholar 

  77. Dupressoir, A. et al. A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast. Proc. Natl Acad. Sci. USA 108, E1164–E1173 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Allis, C. D. & Jenuwein, T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 17, 487–500 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Dean, W., Santos, F. & Reik, W. Epigenetic reprogramming in early mammalian development and following somatic nuclear transfer. Semin. Cell Dev. Biol. 14, 93–100 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Seisenberger, S. et al. The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol. Cell 48, 849–862 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Smallwood, S. A. et al. Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nat. Genet. 43, 811–814 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hamada, H. et al. Allele-specific methylome and transcriptome analysis reveals widespread imprinting in the human placenta. Am. J. Hum. Genet. 99, 1045–1058 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Branco, M. R. et al. Maternal DNA methylation regulates early trophoblast development. Dev. Cell 36, 152–163 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sanchez-Delgado, M. et al. Human oocyte-derived methylation differences persist in the placenta revealing widespread transient imprinting. PLOS Genet. 12, e1006427 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Zhang, Y. et al. Dynamic epigenomic landscapes during early lineage specification in mouse embryos. Nat. Genet. 50, 96–105 (2018). This is a comprehensive study of transcriptomes and base-resolution DNA methylomes during early-lineage specification in peri- and post-implantation mouse embryos.

    Article  CAS  PubMed  Google Scholar 

  86. Smith, Z. D. et al. Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer. Nature 549, 543–547 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Gamage, T. et al. Human trophoblasts are primarily distinguished from somatic cells by differences in the pattern rather than the degree of global CpG methylation. Biol. Open 7, bio034884 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Robinson, W. P. & Price, E. M. The human placental methylome. Cold Spring Harb. Perspect. Med. 5, a023044 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Schroeder, D. I. et al. The human placenta methylome. Proc. Natl Acad. Sci. USA 110, 6037–6042 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bianco-Miotto, T. et al. Recent progress towards understanding the role of DNA methylation in human placental development. Reproduction 152, R23–R30 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Novakovic, B. et al. Wide-ranging DNA methylation differences of primary trophoblast cell populations and derived cell lines: implications and opportunities for understanding trophoblast function. Mol. Hum. Reprod. 17, 344–353 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Wilson, R. L. et al. Characterization of 5-methylcytosine and 5-hydroxymethylcytosine in human placenta cell types across gestation. Epigenetics 14, 660–671 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Luo, C., Hajkova, P. & Ecker, J. R. Dynamic DNA methylation: in the right place at the right time. Science 361, 1336–1340 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Decato, B. E., Lopez-Tello, J., Sferruzzi-Perri, A. N., Smith, A. D. & Dean, M. D. DNA methylation divergence and tissue specialization in the developing mouse placenta. Mol. Biol. Evol. 34, 1702–1712 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Mohammed, H. et al. Single-cell landscape of transcriptional heterogeneity and cell fate decisions during mouse early gastrulation. Cell Rep. 20, 1215–1228 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rulands, S. et al. Genome-scale oscillations in DNA methylation during exit from pluripotency. Cell Syst. 7, 63–76.e12 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ficz, G. et al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473, 398–402 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Senner, C. E., Krueger, F., Oxley, D., Andrews, S. & Hemberger, M. DNA methylation profiles define stem cell identity and reveal a tight embryonic-extraembryonic lineage boundary. Stem Cells 30, 2732–2745 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Khoueiry, R. et al. Lineage-specific functions of TET1 in the postimplantation mouse embryo. Nat. Genet. 49, 1061–1072 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Chrysanthou, S. et al. A critical role of TET1/2 proteins in cell-cycle progression of trophoblast stem cells. Stem Cell Rep. 10, 1355–1368 (2018).

    Article  CAS  Google Scholar 

  101. Dawlaty, M. M. et al. Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9, 166–175 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Schoenfelder, S. et al. Divergent wiring of repressive and active chromatin interactions between mouse embryonic and trophoblast lineages. Nat. Commun. 9, 4189 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Fogarty, N. M., Burton, G. J. & Ferguson-Smith, A. C. Different epigenetic states define syncytiotrophoblast and cytotrophoblast nuclei in the trophoblast of the human placenta. Placenta 36, 796–802 (2015).

    Article  CAS  PubMed  Google Scholar 

  104. Ng, R. K. et al. Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5. Nat. Cell Biol. 10, 1280–1290 (2008). This study identifies the transcription factor Elf5 as an important broker of the first cell fate decision by epigenetic repression in the embryonic lineage, which provides a pioneering molecular example underpinning Waddington’s model of the canalization of developmental pathways.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Dodge, J. E., Kang, Y. K., Beppu, H., Lei, H. & Li, E. Histone H3-K9 methyltransferase ESET is essential for early development. Mol. Cell. Biol. 24, 2478–2486 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yeap, L. S., Hayashi, K. & Surani, M. A. ERG-associated protein with SET domain (ESET)–Oct4 interaction regulates pluripotency and represses the trophectoderm lineage. Epigenetics Chromatin 2, 12 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Yuan, P. et al. Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stem cells. Genes Dev. 23, 2507–2520 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Tachibana, M. et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 16, 1779–1791 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. O'Carroll, D. et al. The polycomb-group gene Ezh2 is required for early mouse development. Mol. Cell. Biol. 21, 4330–4336 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Pasini, D., Bracken, A. P., Jensen, M. R., Lazzerini Denchi, E. & Helin, K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 23, 4061–4071 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Rugg-Gunn, P. J., Cox, B. J., Ralston, A. & Rossant, J. Distinct histone modifications in stem cell lines and tissue lineages from the early mouse embryo. Proc. Natl Acad. Sci. USA 107, 10783–10790 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Alder, O. et al. Ring1B and Suv39h1 delineate distinct chromatin states at bivalent genes during early mouse lineage commitment. Development 137, 2483–2492 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lewis, A. et al. Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation. Nat. Genet. 36, 1291–1295 (2004). This landmark study highlights a lesser, albeit not insignificant, reliance of trophoblast cells on DNA methylation than in embryonic tissues.

    Article  CAS  PubMed  Google Scholar 

  114. Umlauf, D. et al. Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes. Nat. Genet. 36, 1296–1300 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Wagschal, A. & Feil, R. Genomic imprinting in the placenta. Cytogenet. Genome Res. 113, 90–98 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. Sakaue, M. et al. DNA methylation is dispensable for the growth and survival of the extraembryonic lineages. Curr. Biol. 20, 1452–1457 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Yang, X. et al. Silencing of developmental genes by H3K27me3 and DNA methylation reflects the discrepant plasticity of embryonic and extraembryonic lineages. Cell Res. 28, 593–596 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Nugent, B. M., O'Donnell, C. M., Epperson, C. N. & Bale, T. L. Placental H3K27me3 establishes female resilience to prenatal insults. Nat. Commun. 9, 2555 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Inoue, A., Jiang, L., Lu, F., Suzuki, T. & Zhang, Y. Maternal H3K27me3 controls DNA methylation-independent imprinting. Nature 547, 419–424 (2017).

    Article  CAS  PubMed  Google Scholar 

  120. Hanna, C. W. et al. Pervasive polymorphic imprinted methylation in the human placenta. Genome Res. 26, 756–767 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Xu, J. & Kidder, B. L. KDM5B decommissions the H3K4 methylation landscape of self-renewal genes during trophoblast stem cell differentiation. Biol. Open 7, bio031245 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Fedorov, O. et al. Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance. Sci. Adv. 1, e1500723 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Paauw, N. D. et al. H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction. Clin. Epigenetics 10, 85 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hepp, P. et al. Histone H3 lysine 9 acetylation is downregulated in GDM placentas and calcitriol supplementation enhanced this effect. Int. J. Mol. Sci. 19, 4061 (2018).

    Article  PubMed Central  Google Scholar 

  125. Lee, E. Y. et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359, 288–294 (1992).

    Article  CAS  PubMed  Google Scholar 

  126. Clarke, A. R. et al. Requirement for a functional Rb-1 gene in murine development. Nature 359, 328–330 (1992).

    Article  CAS  PubMed  Google Scholar 

  127. Davis, A. C., Wims, M., Spotts, G. D., Hann, S. R. & Bradley, A. A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev. 7, 671–682 (1993).

    Article  CAS  PubMed  Google Scholar 

  128. Wu, L. et al. Extra-embryonic function of Rb is essential for embryonic development and viability. Nature 421, 942–947 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Dubois, N. C. et al. Placental rescue reveals a sole requirement for c-Myc in embryonic erythroblast survival and hematopoietic stem cell function. Development 135, 2455–2465 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Ayadi, A. et al. Mouse large-scale phenotyping initiatives: overview of the European Mouse Disease Clinic (EUMODIC) and of the wellcome trust sanger institute mouse genetics project. Mamm. Genome 23, 600–610 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  131. de Angelis, M. H. et al. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics. Nat. Genet. 47, 969–978 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. White, J. K. et al. Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. Cell 154, 452–464 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Dickinson, M. E. et al. High-throughput discovery of novel developmental phenotypes. Nature 537, 508–514 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Adams, R. H. et al. Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol. Cell 6, 109–116 (2000).

    Article  CAS  PubMed  Google Scholar 

  135. Barak, Y. et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol. Cell 4, 585–595 (1999). This study is one of the first to highlight the connection between placenta and heart development and to prove that a defective placenta can be the sole cause of cardiac defects in the mouse.

    Article  CAS  PubMed  Google Scholar 

  136. O'Keeffe, G. W. & Kenny, L. C. Predicting infant neurodevelopmental outcomes using the placenta? Trends Mol. Med. 20, 303–305 (2014).

    Article  PubMed  Google Scholar 

  137. Hodyl, N. A. et al. Child neurodevelopmental outcomes following preterm and term birth: what can the placenta tell us? Placenta 57, 79–86 (2017).

    Article  CAS  PubMed  Google Scholar 

  138. Maltepe, E. & Fisher, S. J. Placenta: the forgotten organ. Annu. Rev. Cell Dev. Biol. 31, 523–552 (2015).

    Article  CAS  PubMed  Google Scholar 

  139. Bonnin, A. et al. A transient placental source of serotonin for the fetal forebrain. Nature 472, 347–350 (2011). This study identifies that, in both mouse and humans, the placenta acts as a neuroendocrine organ by producing serotonin, a molecule critical for neurodevelopment in the fetus, thus offering a mechanism connecting placental insufficiency with diminished postnatal cognitive abilities and later-life mental health issues.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Ho, L. et al. ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice. Science 357, 707–713 (2017).

    Article  CAS  PubMed  Google Scholar 

  141. Beccari, L. et al. Multi-axial self-organization properties of mouse embryonic stem cells into gastruloids. Nature 562, 272–276 (2018).

    Article  CAS  PubMed  Google Scholar 

  142. Jones, H. N. et al. Hypoplastic left heart syndrome is associated with structural and vascular placental abnormalities and leptin dysregulation. Placenta 36, 1078–1086 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Matthiesen, N. B. et al. Congenital heart defects and indices of placental and fetal growth in a nationwide study of 924 422 liveborn infants. Circulation 134, 1546–1556 (2016).

    Article  PubMed  Google Scholar 

  144. Rychik, J. et al. Characterization of the placenta in the newborn with congenital heart disease: distinctions based on type of cardiac malformation. Pediatr. Cardiol. 39, 1165–1171 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Yoney, A. et al. WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids. eLife 7, e38279 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Fogarty, N. M. E. et al. Genome editing reveals a role for OCT4 in human embryogenesis. Nature 550, 67–73 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Sozen, B. et al. Self-assembly of embryonic and two extra-embryonic stem cell types into gastrulating embryo-like structures. Nat. Cell Biol. 20, 979–989 (2018). This study highlights that mouse gastrulation stage embryo-like structures can self-assemble from the three component stem cell populations (that is, embryonic, extra-embryonic endoderm and trophoblast stem cells) under specific conditions, thereby creating the possibility of studying very early post-implantation-like stages in vitro.

    Article  CAS  PubMed  Google Scholar 

  149. Harrison, S. E., Sozen, B., Christodoulou, N., Kyprianou, C. & Zernicka-Goetz, M. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro. Science 356, eaal1810 (2017).

    Article  PubMed  CAS  Google Scholar 

  150. Rivron, N. C. et al. Blastocyst-like structures generated solely from stem cells. Nature 557, 106–111 (2018). This detailed study demonstrates that the assembly of embryonic and trophoblast stem cells in optimal ratios enables the formation of blastocyst-like structures that provide an ideal tool to study embryonic–trophoblast cell interactions.

    Article  CAS  PubMed  Google Scholar 

  151. Rivron, N. et al. Debate ethics of embryo models from stem cells. Nature 564, 183–185 (2018).

    Article  CAS  PubMed  Google Scholar 

  152. Turco, M. Y. et al. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat. Cell Biol. 19, 568–577 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).

    Article  CAS  PubMed  Google Scholar 

  154. Hata, K., Okano, M., Lei, H. & Li, E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 129, 1983–1993 (2002).

    Article  CAS  PubMed  Google Scholar 

  155. Reik, W., Dean, W. & Walter, J. Epigenetic reprogramming in mammalian development. Science 293, 1089–1093 (2001).

    Article  CAS  PubMed  Google Scholar 

  156. Nikitina, T. et al. Multiple modes of interaction between the methylated DNA binding protein MeCP2 and chromatin. Mol. Cell. Biol. 27, 864–877 (2007).

    Article  CAS  PubMed  Google Scholar 

  157. Maurano, M. T. et al. Role of DNA methylation in modulating transcription factor occupancy. Cell Rep. 12, 1184–1195 (2015).

    Article  CAS  PubMed  Google Scholar 

  158. Dean, W. DNA methylation and demethylation: a pathway to gametogenesis and development. Mol. Reprod. Dev. 81, 113–125 (2014).

    Article  CAS  PubMed  Google Scholar 

  159. Lister, R. et al. Global epigenomic reconfiguration during mammalian brain development. Science 341, 1237905 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Gabel, H. W. et al. Disruption of DNA-methylation-dependent long gene repression in rett syndrome. Nature 522, 89–93 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Lucas, E. S. et al. Loss of endometrial plasticity in recurrent pregnancy loss. Stem Cells 34, 346–356 (2016).

    Article  CAS  PubMed  Google Scholar 

  162. Knofler, M. et al. Human Hand1 basic helix-loop-helix (bHLH) protein: extra-embryonic expression pattern, interaction partners and identification of its transcriptional repressor domains. Biochem. J. 361, 641–651 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Donnison, M., Broadhurst, R. & Pfeffer, P. L. Elf5 and Ets2 maintain the mouse extraembryonic ectoderm in a dosage dependent synergistic manner. Dev. Biol. 397, 77–88 (2015).

    Article  CAS  PubMed  Google Scholar 

  164. Hu, Y. G. et al. Regulation of DNA methylation activity through Dnmt3L promoter methylation by Dnmt3 enzymes in embryonic development. Hum. Mol. Genet. 17, 2654–2664 (2008).

    Article  CAS  PubMed  Google Scholar 

  165. Etoc, F. et al. A balance between secreted inhibitors and edge sensing controls gastruloid self-organization. Dev. Cell 39, 302–315 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Fonseca, B. M., Correia-da-Silva, G. & Teixeira, N. A. The rat as an animal model for fetoplacental development: a reappraisal of the post-implantation period. Reprod. Biol. 12, 97–118 (2012).

    Article  PubMed  Google Scholar 

  167. Soares, M. J., Chakraborty, D., Karim Rumi, M. A., Konno, T. & Renaud, S. J. Rat placentation: an experimental model for investigating the hemochorial maternal–fetal interface. Placenta 33, 233–243 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Sahgal, N., Canham, L. N., Canham, B. & Soares, M. J. Rcho-1 trophoblast stem cells: a model system for studying trophoblast cell differentiation. Methods Mol. Med. 121, 159–178 (2006).

    PubMed  Google Scholar 

  169. Swanson, A. M. & David, A. L. Animal models of fetal growth restriction: considerations for translational medicine. Placenta 36, 623–630 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Andersen, M. D. et al. in Experimental Animal Models of Human Diseases (ed. B. Ibeh). (IntechOpen, 2018).

  171. Grigsby, P. L. Animal models to study placental development and function throughout normal and dysfunctional human pregnancy. Semin. Reprod. Med. 34, 11–16 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Fischer, B., Chavatte-Palmer, P., Viebahn, C., Navarrete Santos, A. & Duranthon, V. Rabbit as a reproductive model for human health. Reproduction 144, 1–10 (2012).

    Article  CAS  PubMed  Google Scholar 

  173. Tan, T. et al. Generation of trophoblast stem cells from rabbit embryonic stem cells with BMP4. PLOS ONE 6, e17124 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Handwerger, S. et al. Development of the sheep as an animal model to study placental lactogen physiology. J. Pediatr. 87, 1139–1143 (1975).

    Article  CAS  PubMed  Google Scholar 

  175. Barry, J. S. & Anthony, R. V. The pregnant sheep as a model for human pregnancy. Theriogenology 69, 55–67 (2008).

    Article  CAS  PubMed  Google Scholar 

  176. Orendi, K. et al. Placental and trophoblastic in vitro models to study preventive and therapeutic agents for preeclampsia. Placenta 32, S49–S54 (2011).

    Article  CAS  PubMed  Google Scholar 

  177. Newby, D., Marks, L., Cousins, F., Duffie, E. & Lyall, F. Villous explant culture: characterization and evaluation of a model to study trophoblast invasion. Hypertens. Pregnancy 24, 75–91 (2005).

    Article  PubMed  Google Scholar 

  178. Sooranna, S. R., Oteng-Ntim, E., Meah, R., Ryder, T. A. & Bajoria, R. Characterization of human placental explants: morphological, biochemical and physiological studies using first and third trimester placenta. Hum. Reprod. 14, 536–541 (1999).

    Article  CAS  PubMed  Google Scholar 

  179. Pattillo, R. A. & Gey, G. O. The establishment of a cell line of human hormone-synthesizing trophoblastic cells in vitro. Cancer Res. 28, 1231–1236 (1968).

    CAS  PubMed  Google Scholar 

  180. Pattillo, R. A., Gey, G. O., Delfs, E. & Mattingly, R. F. Human hormone production in vitro. Science 159, 1467–1469 (1968).

    Article  CAS  PubMed  Google Scholar 

  181. Kohler, P. O. & Bridson, W. E. Isolation of hormone-producing clonal lines of human choriocarcinoma. J. Clin. Endocrinol. Metab. 32, 683–687 (1971).

    Article  CAS  PubMed  Google Scholar 

  182. Hannan, N. J., Paiva, P., Dimitriadis, E. & Salamonsen, L. A. Models for study of human embryo implantation: choice of cell lines? Biol. Reprod. 82, 235–245 (2010).

    Article  CAS  PubMed  Google Scholar 

  183. Graham, C. H. et al. Establishment and characterization of first trimester human trophoblast cells with extended lifespan. Exp. Cell Res. 206, 204–211 (1993).

    Article  CAS  PubMed  Google Scholar 

  184. Choy, M. Y. & Manyonda, I. T. The phagocytic activity of human first trimester extravillous trophoblast. Hum. Reprod. 13, 2941–2949 (1998).

    Article  CAS  PubMed  Google Scholar 

  185. King, A., Thomas, L. & Bischof, P. Cell culture models of trophoblast II: trophoblast cell lines — a workshop report. Placenta 21, S113–S119 (2000).

    Article  PubMed  Google Scholar 

  186. Whitley, G. S. Production of human trophoblast cell lines. Methods Mol. Med. 121, 219–228 (2006).

    PubMed  Google Scholar 

  187. Xu, R. H. et al. BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat. Biotechnol. 20, 1261–1264 (2002).

    Article  CAS  PubMed  Google Scholar 

  188. Zdravkovic, T. et al. Human stem cells from single blastomeres reveal pathways of embryonic or trophoblast fate specification. Development 142, 4010–4025 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors’ programme of work is funded by a Next Generation Fellowship from the Centre for Trophoblast Research to C.W.H.; by a Tier I Canada Research Chair grant to M.H.; by the Magee Prize, funded by the Richard King Mellon Foundation; and by the Alberta Children’s Hospital Research Institute.

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Nature Reviews Genetics thanks S. Paul, J. Rossant and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada

    Myriam Hemberger & Wendy Dean

  2. Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada

    Myriam Hemberger & Wendy Dean

  3. Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada

    Myriam Hemberger

  4. Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge, UK

    Myriam Hemberger, Courtney W. Hanna & Wendy Dean

  5. Centre for Trophoblast Research, University of Cambridge, Cambridge, UK

    Myriam Hemberger & Courtney W. Hanna

  6. Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Canada

    Wendy Dean

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Contributions

W.D. and M.H. contributed to discussion of the content. All authors researched data for the article. The bulk of the article was written by M.H. and W.D., with essential contributions on human development and global epigenome studies by C.W.H. All authors reviewed and/or edited the article before submission.

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Glossary

Trophoblast

The early cell lineage that arises at the blastocyst stage and gives rise to most extra-embryonic tissues, most notably those of the placenta.

Myometrium

The middle layer of the uterine wall, which consists of smooth muscle cells that are important for contraction.

Allogeneic

The phenomenon of cells or tissues being genetically different and hence distinct from each other in terms of cell surface antigen repertoire, leading to immunological incompatibility.

Haemochorial placentation

The anatomical arrangement in placentas in which trophoblast-lined villi are directly exposed to maternal blood.

Decidualization

The process by which endometrial stromal fibroblasts become specialized secretory decidual cells during pregnancy.

Chromatin

The complex of DNA, RNA and proteins (mostly histones) that collectively comprise the chromosomes.

Epigenome

The sum total of all modifications to DNA, or to DNA-associated RNA and proteins, that permit interpretation of the genome to instruct cell identity and function.

Syncytialization

The process of cell–cell fusion that leads to the formation of a multi-nucleate cell. It occurs when cytotrophoblast cells fuse during placental development to form syncytiotrophoblast.

Imprinted genes

The relatively small collection of genes whose expression is solely based on parent-of-origin inheritance of the allele.

Epimutations

Changes in the modification status of a cytosine (that is, DNA methylation, hydroxymethylation or derivatives), usually found in the context of CpG dinucleotides, between successive cell divisions or generations.

Transgenerational inheritance

Inheritance across multiple successive (>2) generations of instructive elements of the epigenome, found in germ cells (oocytes or sperm).

CpG islands

(CGIs). Regions of the genome in which the CpG frequency is greater than 50% GC content over at least 200 base pairs.

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Hemberger, M., Hanna, C.W. & Dean, W. Mechanisms of early placental development in mouse and humans. Nat Rev Genet 21, 27–43 (2020). https://doi.org/10.1038/s41576-019-0169-4

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