Pathway: Replacement of protamines by nucleosomes in the male pronucleus
Reactions in pathway: Replacement of protamines by nucleosomes in the male pronucleus :
Replacement of protamines by nucleosomes in the male pronucleus
In human sperm, about 85 to 90% of the genome is associated with protamines rather than histones (reviewed in Torres-Flores and Hernández-Hernández 2020, Ribas-Maynou et al. 2022). Protamines provide a much higher packing density of DNA in the nucleus but there are few reports of epigenetic marks on protamines (Brunner et al. 2014). After fertilization, protamines in the male pronucleus are replaced with histones provided by the oocyte cytoplasm (reviewed in Yang et al. 2015, Okada and Yamaguchi 2017). The result is a decondensation of sperm chromatin that produces a chromatin state that is permissive for transcription.
Dissociation of protamines from DNA appears to be controlled by phosphorylation of the protamines PRM1 and PRM2 (inferred from mouse homologs in Gou et al. 2020). The kinase SRPK1 phosphorylates both PRM1 and PRM2, which recruit the histone chaperones Nucleoplasmin 2 (NPM2) and HIRA (inferred from mouse homologs in Gou et al. 2020). NPM2 then dissociates the phosphorylated PRM1 from DNA. By inference NPM1 and NPM3, which are also present in the zygote, may also dissociate PRM1 and PRM2 from DNA (Okuwaki et al. 2012).
Nucleosomes in the zygote are characterized by H3.3 and H2AX (H2A.X) (reviewed in Martire and Banaszynski 2020). HIRA chaperones histone H3.3 and acts together with NPM proteins to assemble nucleosomes from individual histone proteins. Asymmetric dimethylation of H3.3 arginine-17 catalyzed by METTL23 is required for assembly of H3.3 into chromatin in the male pronucleus (inferred from mouse homologs in Hatanaka et al. 2017) . The oocyte-specific histone H1, H1FOO (H1.8, H1-8), is also deposited on the newly formed chromatin at this time and persists until the 8-cell stage (McGraw et al. 2006). In mouse embryos, H1foo is not required for development (Sánchez-Sáez et al. 2022).
Dissociation of protamines from DNA appears to be controlled by phosphorylation of the protamines PRM1 and PRM2 (inferred from mouse homologs in Gou et al. 2020). The kinase SRPK1 phosphorylates both PRM1 and PRM2, which recruit the histone chaperones Nucleoplasmin 2 (NPM2) and HIRA (inferred from mouse homologs in Gou et al. 2020). NPM2 then dissociates the phosphorylated PRM1 from DNA. By inference NPM1 and NPM3, which are also present in the zygote, may also dissociate PRM1 and PRM2 from DNA (Okuwaki et al. 2012).
Nucleosomes in the zygote are characterized by H3.3 and H2AX (H2A.X) (reviewed in Martire and Banaszynski 2020). HIRA chaperones histone H3.3 and acts together with NPM proteins to assemble nucleosomes from individual histone proteins. Asymmetric dimethylation of H3.3 arginine-17 catalyzed by METTL23 is required for assembly of H3.3 into chromatin in the male pronucleus (inferred from mouse homologs in Hatanaka et al. 2017) . The oocyte-specific histone H1, H1FOO (H1.8, H1-8), is also deposited on the newly formed chromatin at this time and persists until the 8-cell stage (McGraw et al. 2006). In mouse embryos, H1foo is not required for development (Sánchez-Sáez et al. 2022).
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.