Epigenetic factors in the regulation of prospermatogonia and spermatogonial stem cells

Abstract

Appropriate regulation of epigenome within cells is crucial for the determination of cell fate and contributes to the lifelong maintenance of tissue homeostasis. Epigenomic re-establishment during embryonic prospermatogonia development and fine-tune of the epigenetic landscape in postnatal spermatogonial stem cells (SSCs) are two key processes required for functional male germ cell formation. Repression of re-activated transposons and male germline-specific epigenome establishment occur in prospermatogonia, whereas modulations of the epigenetic landscape is important for SSC self-renewal and differentiation to maintain the stem cell pool and support long-term sperm production. Here, we describe the impact of epigenome-related regulators and small non-coding RNAs as well as the influence of epigenome modifications that result from extrinsic signaling for controlling the decision between self-renewal, differentiation and survival in mouse prospermatogonia and SSCs. This article provides a review of epigenome-related molecules involved in cell fate determination in male germ cells and discusses the intriguing questions that arise from these studies.Reproduction (2015) 150 R77-R91

DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line

“…Differences in DNA methylation are evident between the mitotically arrested prospermatogonia and the derived mitotic, meiotic and postmeiotic germ cells (Oakes et al 2007, Smallwood et al 2011, Kobayashi et al 2012, Niles et al 2013, Molaro et al 2014, Tseng et al 2015. In addition, during spermatogenesis, the chromatin structure in the cells and the expression pattern of ncRNA are dramatically remodeled (Ro et al 2007, Song et al 2011, Shirakata et al 2014.…”

Epigenomic and single-cell profiling of human spermatogonial stem cells

“…Epigenomic and single-cell profiling of human spermatogonial stem cells demonstrate their ability to repopulate the pretreated germ cell free seminiferous tubules and perform full spermatogenesis (8). In humans, xenotransplanting hSSC candidate to busulfan treated mouse testis is the only method.…”

“…Markers for SSC-containing spermatogonia population include THY1, ID4, GFRA1, NANOS2, OCT4, PLZF, and DNMT3L for mice (8,(10)(11)(12)(13)(14), and SSEA4, GFRA1, BCL6, FGFR3, ID4, SALL4, and ETV5 for humans. Only a portion of THY1+ cells or SALL4+ cells, for example, contain SSC activity (15).…”

“…Only a portion of THY1+ cells or SALL4+ cells, for example, contain SSC activity (15). These markers are usually enriched in the A-single to A-align undifferentiated spermatogonia based on whole-mount immunostaining of seminiferous tubules, and are expressed in spermatogonia directly attached to the basal membrane of the seminiferous tubules based on immunohistochemical staining of testis sections (8). With the heterogeneous nature of the spermatogonia population, even the best markers identified so far could contain a certain percentage of SSCs, but not every single cell from the population exhibits full SSC function.…”

“…However, as the current culture system constantly selects for faster proliferating cells, it usually under-represents the quiescent population of SSCs, which could be the most critical cell population for long-term male fertility. For example, the DNMT3L+ quiescent SSCs population that compose around a quarter of freshly isolated THY1+ cells in mice (8,14) cannot be found in cultured SSCs. On the other hand, applying 3D culture/printing technology that merges biomaterial with germ cells or even somatic cells to reconstruct the hSSC niche may provide new hope, since certain extracellular matrix components and biomaterials tend to guide stem cells back into a quiescent status (29,30).…”