Epigenetic priming in the male germline

Abstract

Epigenetic priming presets chromatin states that allow the rapid induction of gene expression programs in response to differentiation cues. In the germline, it provides the blueprint for sexually dimorphic unidirectional differentiation. In this review, we focus on epigenetic priming in the mammalian male germline and discuss how cellular memories are regulated and inherited to the next generation. During spermatogenesis, epigenetic priming predetermines cellular memories that ensure the lifelong maintenance of spermatogonial stem cells and their subsequent commitment to meiosis and to the production of haploid sperm. The paternal chromatin state is also essential for the recovery of totipotency after fertilization and contributes to paternal epigenetic inheritance. Thus, epigenetic priming establishes stable but reversible chromatin states during spermatogenesis and enables epigenetic inheritance and reprogramming in the next generation.

Figure 1

The overview of male germline development in mice. PGCs emerge from the epiblast at E6.25. During their subsequent migration to the gonads, global DNA demethylation takes place. DNA de novo methylation and mitotic arrest occur approximately from E13.5 to P0.5. After birth, prospermatogonia either undergo the first wave of spermatogenesis or give rise to a pool of foundational SSCs. Undifferentiated spermatogonia differentiate into differentiating spermatogonia in response to retinoic acid, and subsequently, they initiate meiosis and undergo two cell divisions, ultimately forming haploid sperm. Key transcriptional regulators are indicated at the bottom.

Figure 2

Epigenetic priming in the male germline: the lunch box model. (a) Bivalent domains marked with both H3K4me2/3 and H3K27me3 are formed at promoters of embryonic developmental genes suppressed throughout the germline and somatic genes suppressed during late spermatogenesis. (b) Meiotic SEs, which facilitate the transcriptional burst in pachytene spermatocytes, are formed by A-MYB. (c) Alterations in 3D chromatin structure during spermatogenesis. (d) The lunch box model of epigenetic priming in spermatogenesis. The differentiation program of late spermatogenesis (especially the burst of gene expression in pachytene spermatocytes) is preset at the chromatin level in spermatogonia. This is akin to the meal that is already prepared in the lunch box. Once differentiation cues are received, differentiation is initiated. The lunch box lid is opened. Gene expression after fertilization is also preprogrammed in the germline at the chromatin level. The copyright of the illustration is attributed to Takashi Mifune (https://www.irasutoya.com/).