Epigenetic regulation of germ cells-remember or forget?

Abstract

Unlike somatic cells, germ cells retain the potential to reproduce an entire new organism upon fertilization. In order to accomplish the process of fertilization, germ cells undergo an extreme cellular differentiation process known as gametogenesis in order to produce morphologically and functionally distinct oocyte and sperm. In addition to changes in genetic content changes from diploid to haploid, epigenetic mechanisms that modify chromatin state without altering primary DNA sequences have profound influence on germ cell differentiation and moreover, the transgenerational effect. In this review, we will go over the most recent discoveries on epigenetic regulations in germline differentiation and transgenerational inheritance across different metazoan species.

Figure 1. Non-random segregation of sister chromatids and histone H3 during asymmetric division of GSCs

Asymmetric GSC division gives rise to two daughter cells: a self-renewed GSC (green) and a differentiating daughter cell (yellow). During this division, mother and daughter centrosomes with distinct microtubule nucleating capabilities are asymmetric inherited; sister chromatids of X and Y chromosomes are segregated non-randomly; and preexisting H3 are preferentially segregated to GSC while newly synthesized H3 are mainly segregated to the other differentiating daughter cell. Potential crosstalk between non-random segregation of sex chromosome sister chromatids and preexisting vs. newly synthesized H3 might exist.

Figure 2. Non-cell-autonomous regulation of germline through somatic gonadal cells

In somatic cells of Drosophila testis, H3K27me3-methyltransferase E(z) might maintain germ cell fate through downstream signaling, such as Wnt or Egfr pathway(s). Egfr signaling can also be regulated by nuclear lamina to promote germ cell differentiation. The H3K27me3 demethylase dUTX can modulate JAK-STAT signaling through activating JAK-STAT signaling inhibitor Socs36E. In addition, chromatin remodeling complex component, such as Nurf301, cooperates with ecdysone signaling to maintain GSCs. In Drosophila ovary, BMP signaling directly repress transcription of differentiation-promoting gene to maintain GSCs. In escort cells, H3K9me3-methyltransferase Eggless and H3K4me1/2-demethylase Lsd1 prevent ectopic BMP signaling outside the niche to regulate germline differentiation.

Figure 3. Transgenerational epigenetic inheritance in multiple organisms

In Drosophila, maternal piRNAs are transmitted to the next generation, whose function is important for transposon silencing in germline to maintain fertility. In addition, they also lead to H3K9me3 at piRNA clusters to promote piRNA biogenesis. In C. elegans, maternal and paternal PRC2-generated H3K27me3 can both be transmitted to embryos. Without the PRC2 enzyme, the H3K27me3 repressive mark only persists for several rounds of cell divisions. Different from H3K27me3, H3K4me2 needs to be erased by the Spr5 demethylase in germ cells at each generation. Failure of erasure leads to heritable accumulation of H3K4me2 and misregulation of spermatogenesis gene expression in germ cells over 20 generations. Multiple chromatin factors, including H3K4me1/me2 and H3K9me3 methyltransferase, H3K9me3 demethylase, and H3K9me reader, can enhance or repress the sterility phenotype of spr-5. In Zebrafish, paternal DNA methylation pattern is maintained during embryo development, while the maternal DNA methylome undergoes reprogramming to resemble the paternal methylome.