Pathway: Chromatin modifications during the maternal to zygotic transition (MZT)
Reactions in pathway: Chromatin modifications during the maternal to zygotic transition (MZT) :
Chromatin modifications during the maternal to zygotic transition (MZT)
Chromatin in the zygotic pronuclei transitions to a more open and accessible conformation by DNA demethylation and changes to histone modifications. As development proceeds through the cleavage stages to the blastocyst, chromatin continues to become more accessible until DNA methylation and a more restrictive chromatin conformation are re-established after implantation of the embryo in the uterus.
In the oocyte, H3K9me2 produced by EHMT2 (G9a, KMT1C) and H3K9me3 produced by SETDB1 (KMT1E) are transmitted to the female pronucleus of the zygote and protect maternal DNA from active demethylation (inferred from mouse zygotes in Zeng et al. 2019, reviewed in de Macedo et al. 2021). DPPA3 binds H3K9me2, preventing the 5-methylcytosine oxidase TET3 from being recruited to chromatin (inferred from mouse homologs in Nakamura et al. 2007, Wossidlo et al. 2011, Nakamura et al. 2012). DPPA3 also displaces UHRF1 from chromatin, preventing the maintenance DNA methylase DNMT1 from being recruited to chromatin and thus allowing passive DNA demethylation to occur in the female genome (inferred from mouse homologs in Funaki et al. 2014, Li et al. 2018, Du et al. 2019, Mulholland et al. 2020).
In the male pronucleus of the zygote, AICDA (AID) deaminates cytosine residues and long patch repair replaces the mismatches and adjacent 5-methylcytidine residues with cytidine (Santos et al. 2013, Franchini et al. 2014). After this initial demethylation, TET3 is recruited to chromatin by METTL23 and STGP4 (GSE) (inferred from mouse homologs in Hatanaka et al. 2017) where it oxidizes remaining 5-methylcytidine to 5-hydroxymethylcytidine, which is removed by base excision repair and replaced with cytidine (inferred from mouse homologs in Gu et al. 2011, Iqbal et al. 2011, Wossidlo et al. 2011, Santos et al. 2013, Amouroux et al. 2016, Hatanaka et al. 2017).
The repressive mark H3K27me3 decreases in 2-cell embryos near developmentally related genes (Xia et al. 2019). The H3K27me3 demethylases KDM6B (inferred from bovine embryos in Chung et al. 2017, Canovas et al. 2012) and KDM6A (inferred from mouse embryos in Bai et al. 2019) appear to play a role in the decrease of H3K27me3, as downregulation of them impairs H3K27me3 loss, zygotic genome activation, and embryonic development. Embryonic development also requires H3K36me3, a permissive mark located in transcribed gene bodies that is produced in the oocyte by SETD2 (inferred from mouse embryos in Xu et al. 2019).
In mouse oocytes, H3K4me3 occurs in unusually broad regions that span genes Dahl et al. 2016, Zhang et al. 2016). These broad regions persist in the zygote and into the 2-cell stage. In the late 2-cell stage the more usual patterns of H3K4me3 are established as sharp peaks of H3K4me3 near the transcription start sites and stop sites of genes. The histone methyltransferase KMT2B is at least partly responsible for establishing the broad regions of H3K4me3 in the oocyte and the histone demethylases KDM5B and KDM5A remove the broad H3K4me3 in the late 2-cell stage embryo (inferred from mouse homologs in Dahl et al. 2016, reviewed in Eckerseley-Maslin et al. 2018).
In human oocytes and zygotes, however, broad regions of H3K4me3 are not observed across genes but are located across distal, CpG-rich domains which have partial DNA methylation (Xia et al. 2019). At the 8-cell stage, expression of KDM5B increases and the H3K4me3 at the distal domains is lost as zygotic genome activation occurs, suggesting a role for KDM5B in loss of H3K4me3 (Xia et al. 2019).
In the oocyte, H3K9me2 produced by EHMT2 (G9a, KMT1C) and H3K9me3 produced by SETDB1 (KMT1E) are transmitted to the female pronucleus of the zygote and protect maternal DNA from active demethylation (inferred from mouse zygotes in Zeng et al. 2019, reviewed in de Macedo et al. 2021). DPPA3 binds H3K9me2, preventing the 5-methylcytosine oxidase TET3 from being recruited to chromatin (inferred from mouse homologs in Nakamura et al. 2007, Wossidlo et al. 2011, Nakamura et al. 2012). DPPA3 also displaces UHRF1 from chromatin, preventing the maintenance DNA methylase DNMT1 from being recruited to chromatin and thus allowing passive DNA demethylation to occur in the female genome (inferred from mouse homologs in Funaki et al. 2014, Li et al. 2018, Du et al. 2019, Mulholland et al. 2020).
In the male pronucleus of the zygote, AICDA (AID) deaminates cytosine residues and long patch repair replaces the mismatches and adjacent 5-methylcytidine residues with cytidine (Santos et al. 2013, Franchini et al. 2014). After this initial demethylation, TET3 is recruited to chromatin by METTL23 and STGP4 (GSE) (inferred from mouse homologs in Hatanaka et al. 2017) where it oxidizes remaining 5-methylcytidine to 5-hydroxymethylcytidine, which is removed by base excision repair and replaced with cytidine (inferred from mouse homologs in Gu et al. 2011, Iqbal et al. 2011, Wossidlo et al. 2011, Santos et al. 2013, Amouroux et al. 2016, Hatanaka et al. 2017).
The repressive mark H3K27me3 decreases in 2-cell embryos near developmentally related genes (Xia et al. 2019). The H3K27me3 demethylases KDM6B (inferred from bovine embryos in Chung et al. 2017, Canovas et al. 2012) and KDM6A (inferred from mouse embryos in Bai et al. 2019) appear to play a role in the decrease of H3K27me3, as downregulation of them impairs H3K27me3 loss, zygotic genome activation, and embryonic development. Embryonic development also requires H3K36me3, a permissive mark located in transcribed gene bodies that is produced in the oocyte by SETD2 (inferred from mouse embryos in Xu et al. 2019).
In mouse oocytes, H3K4me3 occurs in unusually broad regions that span genes Dahl et al. 2016, Zhang et al. 2016). These broad regions persist in the zygote and into the 2-cell stage. In the late 2-cell stage the more usual patterns of H3K4me3 are established as sharp peaks of H3K4me3 near the transcription start sites and stop sites of genes. The histone methyltransferase KMT2B is at least partly responsible for establishing the broad regions of H3K4me3 in the oocyte and the histone demethylases KDM5B and KDM5A remove the broad H3K4me3 in the late 2-cell stage embryo (inferred from mouse homologs in Dahl et al. 2016, reviewed in Eckerseley-Maslin et al. 2018).
In human oocytes and zygotes, however, broad regions of H3K4me3 are not observed across genes but are located across distal, CpG-rich domains which have partial DNA methylation (Xia et al. 2019). At the 8-cell stage, expression of KDM5B increases and the H3K4me3 at the distal domains is lost as zygotic genome activation occurs, suggesting a role for KDM5B in loss of H3K4me3 (Xia et al. 2019).
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)
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)
As early steps towards capturing the array of processes by which a fertilized egg gives rise to the diverse tissues of the body, examples of several processes have been annotated. Aspects of processes involved in most developmental processes, transcriptional regulation of pluripotent stem cells, gastrulation, and activation of HOX genes during differentiation are annotated. More specialized processes include nervous system development , aspects of the roles of cell adhesion molecules in axonal guidance and myogenesis, transcriptional regulation in pancreatic beta cell, cardiogenesis, transcriptional regulation of granulopoeisis, transcriptional regulation of testis differentiation, transcriptional regulation of white adipocyte differentiation, and molecular events of "nodal" signaling, LGI-ADAM interactions, and keratinization.