The germline is the only cellular lineage capable of transmitting genetic and epigenetic information to the next generation. In the mammalian germline, primordial germ cells (PGCs), the precursors of sperm and eggs, are specified in the early embryos and undergo epigenetic reprogramming to reset previous epigenetic states [1]. Upon migration to the gonads, PGCs receive sex-specific signals from the surrounding somatic cells, which initiate either spermatogenesis or oogenesis [2]. After reaching the gonad, male germ cells are called prospermatogonia (also known as gonocytes) and arrest at the G1/G0 phase of the cell cycle. Prospermatogonia later resume the cell cycle after birth, and a subset of them convert to spermatogonial stem cells (SSCs), which sustain the lifelong production of sperm [3]. After the commitment to differentiation, male germ cells undergo meiosis and produce haploid sperm (Figure 1) [4]. Although single-cell RNA-seq analysis revealed various substages and transitions during spermatogenesis [5], the final cell fate of male germ cells after sex determination is sperm unless the cells undergo cell death [6]. Consistent with this unidirectionality of the differentiation process, recent studies revealed that gene expression programs in various stages of spermatogenesis are predetermined at the chromatin level during prior stages of development 7, 8, 9, 10 (Figure 2). This suggests that chromatin-based cellular memories ensure the unidirectional differentiation process during spermatogenesis.

Another major aspect of epigenetic regulation in the germline is the preparation for embryonic development in the next generation. Several studies demonstrate that the chromatin state of sperm contributes to the transmission of epigenetic information to the offspring 11, 12, 13••. Epigenomic instability in sperm is associated with an increased risk of abnormal embryogenesis, highlighting the importance of the paternal epigenome in embryonic development 11, 14.

Epigenetic priming, observed in a variety of cell types such as pluripotent stem cells, neurons, immune cells, and cancer cells, presets chromatin states that enable the induction of gene expression programs in response to differentiation cues 15, 16, 17, 18. In the male germline, epigenetic priming provides stable but reversible chromatin states that guide unidirectional spermatogenesis and allow subsequent epigenetic inheritance and reprogramming in the next generation. In this review, we discuss recent findings that highlight the importance of epigenetic priming for autosomal gene expression programs during the major stages of male germline development, as well as for the subsequent epigenetic inheritance and reprogramming in the next generation. For other key aspects of germline development, such as the regulation of the sex chromosomes, retrotransposons, and gene regulation in the female germline, we refer readers to recent reviews on these topics 3, 19, 20, 21, 22.