Epigenetic Regulation during Primordial Germ Cell Development and Differentiation

Abstract

Germline development varies significantly across metazoans. However, mammalian primordial germ cell (PGC) development has key conserved landmarks, including a critical period of epigenetic reprogramming that precedes sex-specific differentiation and gametogenesis. Epigenetic alterations in the germline are of unique importance due to their potential to impact the next generation. Therefore, regulation of, and by, the non-coding genome is of utmost importance during these epigenomic events. Here, we detail the key chromatin changes that occur during mammalian PGC development and how these interact with the expression of non-coding RNAs alongside broader epitranscriptomic changes. We identify gaps in our current knowledge, in particular regarding epigenetic regulation in the human germline, and we highlight important areas of future research.

Epigenetic resetting in the human germ line entails histone modification remodeling

“…In mice, small noncoding RNAs such as piRNAs have been shown to mediate TE repression through H3K9me3 deposition, albeit in later germ cell development ( 56 ). While there are no data supporting an active piRNA pathway in mitotically active hPGCs, other layers of defense, such as tRNA fragments ( 57 ) and RNA modifications ( 58 ), might contribute to TE repression, H3K9me3 deposition, or prevention of transcriptional activation.…”

Taming transposable elements in vertebrates: from epigenetic silencing to domestication

“…As mentioned earlier, in mammals TE silencing mechanisms are particularly crucial during embryogenesis and germ cell specification. During these stages, the genome undergoes two distinct waves of DNA demethylation and reprogramming: early on upon fertilization and later on during germ cell specification [43,44]. This is accompanied by dynamic changes in histone Box 5.…”

“…Such extensive epigenetic reprogramming events may expose the genome to detrimental effects of reactivated TEs, particularly retrotransposons, if left uncontrolled. It is currently unclear whether RNA modifications, sRNAs, or chromatin modifications can compensate for the fluctuations in DNA methylation levels observed during early development, to ensure continuous TE silencing [44]. In line with a compensatory function, recent research in mice suggests a role for H3K9me3 and H4K20me3 in the silencing of long terminal repeat (LTR) retrotransposons in the morula [46].…”

“…Given the difficulty of in vivo approaches during the stages of reprogramming, in vitro inducible genetic perturbation of a combination of epigenetic silencing pathways could be performed, for example, using CRISPR technologies (Box 7). These approaches would also shed light on how some evolutionarily young TEs escape demethylation during reprogramming [44].…”

The Beginning of Meiosis in Mammalian Female Germ Cells: A Never-Ending Story of Intrinsic and Extrinsic Factors

“…It forms the basis to generate extremely specialized female and male germ cells but, at the same time, to set up in them a genomic status sufficiently plastic to rapidly regain, at fertilization, totipotency in the zygote and blastomeres. To learn more about this crucial process, readers can refer to [ 39 ].…”