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Dynamics of the epigenetic landscape during the maternal-to-zygotic transition

Nature Reviews Molecular Cell Biology volume 19, pages 436–450 (2018)Cite this article

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Abstract

A remarkable epigenetic remodelling process occurs shortly after fertilization, which restores totipotency to the zygote. This involves global DNA demethylation, chromatin remodelling, genome spatial reorganization and substantial transcriptional changes. Key to these changes is the transition from the maternal environment of the oocyte to an embryonic-driven developmental expression programme, a process termed the maternal-to-zygotic transition (MZT). Zygotic genome activation occurs predominantly at the two-cell stage in mice and the eight-cell stage in humans, yet the dynamics of its control are still mostly obscure. In recent years, partly due to single-cell and low-cell number epigenomic studies, our understanding of the epigenetic and chromatin landscape of preimplantation development has improved considerably. In this Review, we discuss the latest advances in the study of the MZT, focusing on DNA methylation, histone post-translational modifications, local chromatin structure and higher-order genome organization. We also discuss key mechanistic studies that investigate the mode of action of chromatin regulators, transcription factors and non-coding RNAs during preimplantation development. Finally, we highlight areas requiring additional research, as well as new technological advances that could assist in eventually completing our understanding of the MZT.

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Fig. 1: Overview of transcription and DNA methylation dynamics during mouse preimplantation development.
Fig. 2: Dynamics of chromatin landscapes during preimplantation development.
Fig. 3: Regulation of the maternal-to-zygotic transition by histone-modifying enzymes and non-coding RNAs.
Fig. 4: Models of event hierarchies leading to the major wave of ZGA.

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Acknowledgements

The authors thank W. Dean, C. Hanna, F. Santos, I. Herraez and T. Lohoff for careful reading of the manuscript. The authors apologize to all authors of studies they could not cite given the concise nature of this Review. M.A.E.-M. is supported by a Marie Sklodowska-Curie Individual Fellowship, and C.A.-C. is supported by a postgraduate award by the Biotechnology and Biological Sciences Research Council (BBSRC). The laboratory of W.R. is supported by the BBSRC (BB/K010867/1), the Wellcome Trust (095645/Z/ 11/Z), EU BLUEPRINT and EpiGeneSys.

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  1. These authors contributed equally: Melanie A. Eckersley-Maslin, Celia Alda-Catalinas.

Authors and Affiliations

  1. Epigenetics Programme, Babraham Institute, Cambridge, UK

    Melanie A. Eckersley-Maslin, Celia Alda-Catalinas & Wolf Reik

  2. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Wolf Reik

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

    Wolf Reik

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M.A.E.-M. and C.A.-C. researched data for the article; M.A.E.-M., C.A.-C. and W.R. made substantial contributions to the discussion of content; M.A.E.-M. and C.A.-C. wrote the article and M.A.E.-M., C.A.-C. and W.R. reviewed and/or edited the manuscript before submission.

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Glossary

Zygote

Diploid, one-cell totipotent embryo formed at fertilization between the egg and sperm. The zygote represents the earliest developmental stage of an embryo.

Pronuclei

Physically separated paternal and maternal nuclei present in the zygote after fertilization, before pronuclear syngamy and the first cleavage division.

Pronuclear syngamy

Process in which the paternal and maternal pronuclei come together in the zygote.

Totipotent

Refers to the ability of a cell to divide and differentiate into any cell type of both embryonic and extra-embryonic origin.

Cleavage divisions

Cell divisions occurring from the zygote to the morula stages, which take place in the absence of cell growth. The progressive decrease in blastomere size with each subsequent division means the net size of the embryo does not change.

Blastocyst

Stage in mammalian preimplantation development immediately before implantation that contains cells arranged in a ball with a central cavity. In mice, at embryonic day 3.5, the blastomeres are located in the inner cell mass or the extra-embryonic trophectoderm.

Pluripotent

Refers to a cell with the developmental capacity to generate any of the three germ layers of the embryo proper (endoderm, ectoderm and mesoderm).

Small non-coding RNAs

(sncRNAs). Short (20–30 nucleotides), non-coding RNAs that can be produced from various precursors and form various classes, including those involved in epigenetic and post-transcriptional gene silencing such as microRNAs.

Long non-coding RNAs

(lncRNAs). Transcripts, typically longer than 200 nucleotides in length, that are not translated into proteins or that lack an open reading frame.

Gastrulation

Stage of early embryonic development in which the blastula is reorganized into a trilaminar structure containing the three germ layers (ectoderm, mesoderm and endoderm).

Maternal-effect genes

(MEGs). Genes expressed, although not necessarily exclusively, in the female germline whose function is essential for embryonic development. Altering the expression of MEGs in the oocyte before fertilization causes developmental defects in the embryo.

Imprinting

Epigenetic phenomenon driven by DNA methylation, in which certain genes are solely expressed from the paternal or the maternal allele. Imprinted genes largely retain their DNA methylation status during epigenetic reprogramming in the early embryo.

Subcortical maternal complex

(SCMC). Cytoplasmic multiprotein complex essential for preimplantation development. It is localized at the subcortex of oocytes and early embryos and excluded from regions of cell-to-cell contact in the cleavage-stage embryo.

Pronuclear stage

The zygote goes through five pronuclear stages, which correlate to cell cycle phases: PN0–PN2 correspond to G1 phase, PN3 and PN4 to S phase and PN5 to G2 phase.

Metaphase II (MII) oocyte

Mature oocyte after ovulation that is arrested in the metaphase of the second meiotic division. MII oocytes have a visible polar body and can be fertilized.

Polycomb repressive complex 2

(PRC2). Complex of evolutionarily conserved proteins primarily catalysing histone H3 Lys27 trimethylation; involved in transcription silencing.

Inner cell mass

(ICM). Group of pluripotent cells in the early mammalian blastocyst (embryonic day 3.5 in mice) able to give rise to all cell types in the embryo, as well as the extra-embryonic primitive endoderm.

Morula

Spherical, solid and polarized cellular mass of blastomeres formed during mammalian preimplantation development after compaction of the eight-cell embryo and before formation of the blastocyst.

Non-surrounded nucleolus

Morphology of germinal vesicle oocytes without a condensed chromatin ring surrounding the nucleolus. Non-surrounded nucleolus oocytes are transcriptionally active.

Surrounded nucleolus

Morphology of germinal vesicle oocytes with a condensed chromatin ring surrounding the nucleolus. Surrounded nucleolus oocytes are transcriptionally quiescent.

Germinal vesicle oocytes

Immature oocytes arrested in the metaphase of the first meiotic division before ovulation. They have a nucleus called a germinal vesicle, which is clearly visible under a light microscope.

Protamines

Small arginine-rich nuclear proteins present in mature sperm, which largely replace histones to allow denser DNA packaging.

Zona pellucida

Specialized extracellular layer of glycoproteins surrounding the plasma membrane of mammalian oocytes. Also known as the egg coat or pellucid zone. It is vital both before and after fertilization.

Polyspermy

Abnormal fertilization phenomenon in which the oocyte is fertilized by more than one spermatozoon, generally resulting in an unviable embryo.

Morpholino

Synthetic oligomer used for gene knockdown. It undergoes base pairing with complementary RNA and inhibits translation. Morpholino bases are attached to a backbone of methylene morpholine rings linked through phosphordiamidate groups instead of phosphates.

Parthenogenetic embryos

Embryos originated from a metaphase II oocyte in the absence of fertilization from sperm. In mammals, parthenogenetic embryos have severe developmental abnormalities and are generally non-viable.

Chromocenter

Large cluster of constitutive heterochromatin visualized in the interphase nucleus as a densely staining region. In the mouse, chromocenter formation first occurs in the two-cell embryo.

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Eckersley-Maslin, M.A., Alda-Catalinas, C. & Reik, W. Dynamics of the epigenetic landscape during the maternal-to-zygotic transition. Nat Rev Mol Cell Biol 19, 436–450 (2018). https://doi.org/10.1038/s41580-018-0008-z

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