Maternal to zygotic transition (MZT)

Stable Identifier
R-HSA-9816359
DOI
10.3180/R-HSA-9816359.1
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Maternal to zygotic transition (MZT)
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Fertilization of the oocyte triggers the maternal-to-zygotic transition (MZT, reviewed in Vastenhous et al. 2019), a series of events that degrades maternal mRNAs (reviewed in Sha et al. 2019), alters chromatin to allow widespread transcription (reviewed in Eckersley-Maslin et al. 2018), and initiates transcription of the new zygotic genome (zygotic genome activation, ZGA, embryonic genome activation, EGA, reviewed in Wu and Vastenhouw 2020).
Immediately after fertilization, the oocyte completes the final stage of the second meiotic division and the resulting zygote contains separate female and male pronuclei. Within the male pronucleus, protamines are replaced by histones provided by the oocyte (reviewed in McLay and Clarke 2003, Yang et al. 2015). A specific set of maternal mRNAs is degraded by maternally provided factors in a process called M-decay (reviewed in Jiang and Fan 2022) and DNA methylation is lost in both the male pronucleus and the female pronucleus. In mouse zygotes, male DNA methylation is lost in an active process in which cytidine deamination by AICDA (AID) and excision repair initially remove 5-methylcytidine residues, then remaining 5-methylcytidine residues are oxidized by TET3 and removed by base excision repair so that male DNA methylation begins to decrease before fusion of the male and female pronuclei. Maternal DNA methylation is passively lost by dilution over subsequent cell generations, yielding a blastocyst that has low male and female DNA methylation (reviewed in Marcho et al. 2015, Eckersley-Maslin et al. 2018). In human embryos, DNA demethylation in male and female genomes is much faster and is complete by the 2-cell stage, suggesting that maternal DNA demethylation may occur at least partly actively (Guo et al. 2014, reviewed in Tesarik 2022).
In mouse embryos, methylation at histone H3 lysine-4 (H3K4me3), a mark of active chromatin, changes from broad regions that span genes in the maternal genome to peaks at the 5' and 3' ends of genes. Acetylation of H3K27, another mark of active chromatin, increases and methylation of H3K27 and H3K9, repressive marks, becomes reduced (reviewed in Marcho et al. 2015, Eckersley-Maslin et al. 2018). The result is a permissive state of chromatin that produces the first transcription of the zygotic genome and continues into the pluripotent cells of the blastocyst.
Activation of transcription of the zygotic genome, called zygotic genome activation (ZGA) or embryonic genome activation (EGA), occurs in two phases: an initial minor phase followed by a major phase (reviewed in Perry et al. 2022). In mouse zygotes and possibly in human zygotes, the minor phase starts at the 1-cell stage. In mice, the major phase occurs at the 2-cell stage; in humans the major phase occurs at the 8-cell stage. Surprisingly, many transcripts in the early embryo originate from the LTRs of endogenous retroviruses. The LTRs later become silenced after implantation of the embryo.
Developmental pluripotency-associated protein 2 (DPPA2), DPPA4, and Double homeobox protein 4 (DUX4, homolog of mouse Dux) are all key transcription factors that participate in initiating the first, minor wave of ZGA. DPPA2 and DPPA4 activate DUX4 and other genes. DUX4 is actually a small array of identical retroposed genes that were produced by reverse transcription in the germline. DUX4 acting with other factors then activates developmental regulators such as ZSCAN4, the double homeobox genes DUXA, DUXB, LEUTX, and the histone demethylase KDM4E. Significantly, DUX4 binds and activates bidirectional transcription from the LTRs of HERVL endogenous retroviruses and Mammalian Apparent LTRs (MaLRs). Interestingly, human DUX4 and its homolog mouse Dux bind species-specific LTRs, indicating that DUX4 and Dux are coevolving with the endogenous retroviruses in their respective genomes (Whiddon et al. 2017). DUX4 also binds and activates bidirectional transcription of species-specific pericentromeric repeats, the human HSATII repeats.
Activation of the zygotic genome produces factors that further degrade maternal mRNAs in a process called Z-decay (reviewed in Jiang and Fan 2022)
Literature References
PubMed ID Title Journal Year
32591075 From mother to embryo: A molecular perspective on zygotic genome activation

Wu, E, Vastenhouw, NL

Curr Top Dev Biol 2020
36182534 The initiation of mammalian embryonic transcription: to begin at the beginning

Asami, M, Lam, BYH, Yeo, GSH, Perry, ACF

Trends Cell Biol 2022
29686419 Dynamics of the epigenetic landscape during the maternal-to-zygotic transition

Reik, W, Alda-Catalinas, C, Eckersley-Maslin, MA

Nat Rev Mol Cell Biol 2018
31189646 The maternal-to-zygotic transition revisited

Cao, WX, Vastenhouw, NL, Lipshitz, HD

Development 2019
30715134 A story of birth and death: mRNA translation and clearance at the onset of maternal-to-zygotic transition in mammals†

Fan, HY, Sha, QQ, Zhang, J

Biol Reprod 2019
28459454 Conservation and innovation in the DUX4-family gene network

Whiddon, JL, Langford, AT, Wong, CJ, Zhong, JW, Tapscott, SJ

Nat Genet 2017
25328107 Maternal histone variants and their chaperones promote paternal genome activation and boost somatic cell reprogramming

Wu, W, Macfarlan, TS, Yang, P

Bioessays 2015
25079557 The DNA methylation landscape of human early embryos

Liu, P, Yong, J, Yan, J, Guo, H, Li, R, Lin, S, Fan, X, Tang, F, Hu, B, Yan, L, Qiao, J, Wu, X, Wang, X, Wen, L, Li, X, Li, J, Jin, X, Wei, Y, Shi, X, Wang, W, Zhu, P, Lian, Y, Xie, SX, Guo, F, Ren, X

Nature 2014
35098307 Five questions toward mRNA degradation in oocytes and preimplantation embryos: when, who, to whom, how, and why?†

Fan, HY, Jiang, ZY

Biol Reprod 2022
12713425 Remodelling the paternal chromatin at fertilization in mammals

McLay, DW, Clarke, HJ

Reproduction 2003
26031750 Epigenetic dynamics during preimplantation development

Mager, J, Cui, W, Marcho, C

Reproduction 2015
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Go Biological Process
maternal-to-zygotic transition of gene expression (0160021)
Authored
May, B  (2022-09-07)
Reviewed
Xie, W  (2023-08-08)
Created
May, B  (2022-09-12)
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