Epigenetic reprogramming during the maternal-to-zygotic transition

Abstract

After fertilization, sperm and oocyte fused and gave rise to a zygote which is the beginning of a new life. Then the embryonic development is monitored and regulated precisely from the transition of oocyte to the embryo at the early stage of embryogenesis, and this process is termed maternal-to-zygotic transition (MZT). MZT involves two major events that are maternal components degradation and zygotic genome activation. The epigenetic reprogramming plays crucial roles in regulating the process of MZT and supervising the normal development of early development of embryos. In recent years, benefited from the rapid development of low-input epigenome profiling technologies, new epigenetic modifications are found to be reprogrammed dramatically and may play different roles during MZT whose dysregulation will cause an abnormal development of embryos even abortion at various stages. In this review, we summarized and discussed the important novel findings on epigenetic reprogramming and the underlying molecular mechanisms regulating MZT in mammalian embryos. Our work provided comprehensive and detailed references for the in deep understanding of epigenetic regulatory network in this key biological process and also shed light on the critical roles for epigenetic reprogramming on embryonic failure during artificial reproductive technology and nature fertilization.

Keywords: MZT; ZGA; chromatin; embryo development; epigenetics; reprogramming.

FIGURE 1

Dynamics of transcriptome during early mouse embryo development. Maternal mRNAs undergo degradation after fertilization, depending on maternal‐factor‐mediated (M‐decay) and zygotic‐factor‐mediated (Z‐decay) pathways. The zygotic genome activation (ZGA) occurs in two successive waves: the minor ZGA and major ZGA.

FIGURE 2

General schematic of epigenetic modifications in eukaryotes. In eukaryotes, DNA methylation is the well‐studied epigenetic modification and occurs at the 5′ position of the cytosine pyrimidine. DNA wraps around histone octamers, forming chromatin in nucleus. Histone modifications mainly consist of methylation, acetylation, ubiquitination, and phosphorylation. Moreover, chromatin is folded and organized three‐dimensionally within the nucleus. Besides, RNA epigenetic modification is intensely studied in recent years. RNA m6A is founded to be the most abundant mRNA modification.

FIGURE 3

Epigenetic reprogramming during early mouse embryo development. Following fertilization, early embryos undergo global DNA demethylation. Maternal noncanonical H3K4me3, H3K27me3 (besides promoter H3K27me3), and H2AK119ub1 are inherited from oocytes, whereas paternal noncanonical histone modifications and maternal noncanonical H3K27ac are de novo established after fertilization. H3K4me3 and H3K27ac are reprogrammed to the canonical patterns at the 2‐cell stage. Noncanonical H3K9me3, H3K27me3, and H2AK119ub1 remain until the blastocyst stage. Compartments A/B and topologically associating domains (TADs) are largely lost after fertilization and become consolidated gradually with the embryo development. Polycomb‐associating domains (PADs) can only be detected in the maternal genome in early embryos and become clear at the 2‐cell stage but absent in blastocysts. Lamina‐associated domains (LADs) exist as a noncanonical pattern on both parental genomes at the 2‐cell stage and reprogrammed to canonical pattern in 8‐cell embryos. Global abundance of m⁶A decreases continuously during mouse maternal‐to‐zygotic transition (MZT) but increases after the 2‐cell stage.

FIGURE 4

Dynamic changes and regulations of histone modifications on the maternal genome during maternal‐to‐zygotic transition (MZT). In MII oocytes, ncH3K4me3 is deposited in both promoters and distal regions, which was mediated through the action of KMT2B and SETD1‐CXXC1. Moreover, ncH3K4me3 is removed by KMT2A/B in 2‐cell stage embryos, facilitating the formation of canonical H3K4me3. Correct distribution of H3K9me3 in oocytes requires SETDB1 and KDM4A. The H3K9me3 at promoter regions is largely removed after fertilization. In zygotes, the deposition of H3K9me3 on maternal genome is mediated by SETDB1 and EHMT2. Both distal domains and promoters are marked by H3K27me3 in MII oocytes. H3K27me3 at promoter of developmental genes is removed after fertilization, but H3K27me3 at distal regions are inherited by the zygote. USP16 and PRC1 ensure the normal distribution of H2AK119ub1 in oocytes. Moreover, PRC1 guides the reestablishment of H2AK119ub after fertilization, occupying both promoter regions and distal regions. Moreover, the H2AK119ub1 is removed from broad distal domains and is deposited in promoter regions. The ncH3K27ac is established after fertilization, and CBP contributes to this process. In 2‐cell stage embryos, HDACs are responsible for the transition of broad H3K27ac domains to narrow peaks.

FIGURE 5

An overview of regulators important for maternal transcriptome degradation during maternal‐to‐zygotic transition. For M‐decay, maternal BTG4 can recruit CCR4‐NOT complex to mRNAs via interacting with the poly(A) binding proteins PABPN1L. ZFP36L2 can also recruit CCR4‐NOT complex to ARE‐containing mRNAs. m⁶A reader also can recruit CCR4‐NOT complex to mRNAs. AGO2 can bind to the mRNAs through endosiRNA. Maternal transcripts undergo Z‐decay tend to have longer 3′‐UTRs and higher translational activity than those undergo Z‐decay. BTG4‐CCR4‐NOT complex also mediated the deadenylation of Z‐decay transcripts and promote the dissociation of PABPC1 from mRNAs. TUT4/7 mediated the uridylation of mRNAs with short poly(A) tails (<25 nucleotides), and DIS3L2 which recruited by PABPN1 is important for the degradation of oligouridylated mRNAs.

FIGURE 6

An overview of pioneer transcript factors important for zygotic genome activation (ZGA) initiation. NR5A2 and ESRRB can bind to the SINE B1/Alu retrotransposons to increase chromatin accessibility and regulate ZGA genes expression. NFYA can bind to CCAAT motif to increase chromatin accessibility and regulate ZGA gene expression. MLX and RFX1 play important roles in nucleosome‐depleted region (NDR) formation to regulate ZGA gene expression.