Similarity of epigenetic reprogramming in primordial germ cells between human and mouse

Abstract

Germ cells have a unique ability to produce a new individual and are paramount for transmitting intact genome and appropriate epigenome from generation to generation. Primordial germ cells (PGCs), the first germ cell population established in the embryo, undergo sequential epigenetic reprogramming to ensure the fidelity of this transmission. Although the developmental and epigenetic processes in mouse PGCs are well understood, antithetically our knowledge in human PGCs remains elusive. Recently, three research teams coincidently discovered the transcriptome and DNA methylome of human PGCs by single-cell RNA-sequencing and whole-genome bisulfite sequencing, providing a fundamental framework for understanding human germline epigenetic reprogramming during embryonic development and its biological outcome [1–3]. One of the teams, led by Fuchou Tang and Jie Qiao at Peking University in China, analyzed the transcriptome and DNAmethylome of PGCs from 4to 19week-old human embryos and provided four key insights [2]. First, the transcriptomes of early human PGCs were generally stable between 4 and 11 weeks of development. Only after 17 weeks the heterogeneity of gene expressionoccured in meiotic female PGCs, indicating entry into meiosis asynchronously. However, the inactivated X chromosome was reactivated in human PGCs as early as 4 weeks. Second, global DNA demethylation in human PGCs was much more thorough than that of preimplantation embryos, and happened in gene body regions, the surrounding intergenic regions, functional genomic elements and CpG islands. However, the evolutionarily younger and more active transposable elements evaded global DNA demethylaion in human PGCs and retained high levels of residual DNA methylation, implying potential role for transgenerational epigenetic inheritance as the other group suggested [3].Third, extensive erasure of the methylation of imprinted genes occurred in early humanPGCs and wasmaintaineduntil 19weeks.Lastly, the study showed that there was strong enrichment of the base-excision mismatch repair (BER) pathway in human PGCs, denoting the possibility of global DNA demethylation being contributed by the BER pathway. A comparison of the methylomes between human and mouse PGCs reveals high conservation of epigenetic reprograming, with overall similar genomewide DNA demethylation dynamics in human migrating and gonadal PGCs and those of mouse PGCs at comparable stages.Mechanistically, BER pathway enrichment has been also observed at similar stages of PGCs in mouse [4,5], implying human and mouse may share same BER-involved DNA demethylation mechanisms. With the detailed map of transcriptome and DNA methylome, the next challenge will be to elucidate the underlying mechanisms behind epigenetic regulation during human PGC development. It remains to be clarified how global DNA demethylation does not result in deregulation gene transcription in PGCs. The functional link between regions resistant to DNA demethylation and transgenerational epigenetic inheritanceneeds tobe further defined in future work.More specifically,what is themechanism for driving escape from global erasure of DNA methylation during human PGCdevelopment?As humanPGCsamples remain scarce, achieving a mechanistic understanding of epigenetic regulation in human PGCs will be difficult. However, given the similarity between DNA methylation dynamics in mouse and human PGCs, mouse PGCs should provide a valuable model for uncovering themechanismsof epigenetic reprogramming in human PGCs.