The mammalian germline as a pluripotency cycle

Abstract

SummaryNaive pluripotency refers to the capacity of single cells in regulative embryos to engender all somatic and germline cell types. Only germ cells -conventionally considered to be unipotent -can naturally re-acquire pluripotency, by cycling through fertilisation. Furthermore, primordial germ cells express, and appear to be functionally dependent upon, transcription factors that characterise the pluripotent state. We hypothesise that germ cells require pluripotency factors to control a derestricted epigenome. Consequently, they harbour latent potential, as manifested in teratocarcinogenesis or direct conversion into pluripotent stem cells in vitro. Thus, we suggest that there exists an unbroken cycle of pluripotency, naive in the early epiblast and latent in the germline, that is sustained by a shared transcription factor network.

A set of genes critical to development is epigenetically poised in mouse germ cells from fetal stages through completion of meiosis

“…Loss of the poised state at some or all of these genes corresponds to differentiation, and to the transition from immortal germ line to mortal soma or extraembryonic tissue. The concept of "latent pluripotency," or continuous retention of a state conducive to establishment of tissues belonging to the three germ layers, has recently been proposed as a unifying feature of the germ line (6). We now suggest that the germ line is unified by a poised nuclear state that enables establishment not just of pluripotency, but of totipotency following fertilization.…”

“…In many species, a specialized cytoplasm, often referred to as the "germ plasm," provides biochemical continuity and helps define the germ line (3,4), but mammals lack a well-defined germ plasm; mammalian germ cells are instead specified from multipotent tissue during embryogenesis. It is therefore unclear whether the potential to contribute to a new individual can be connected to any consistent molecular features in the mammalian germ line (5,6).…”

Poised chromatin in the mammalian germ line

“…Others have proposed that germ cells are specified from a mesodermal intermediate at this point (Kurimoto et al, 2008;Hayashi and Surani, 2009;Aramaki et al, 2013). Demonstrating that poised chromatin is retained at developmental genes corresponding to all somatic lineages in E6.5-E7.5 germ cells would support the model that the germ line remains segregated from soma throughout this period (Leitch and Smith, 2013). Fifth, the extent to which the poised gene complements of the maternal and paternal germ lines diverge has yet to be evaluated; poising of different gene sets in the male and female germ lines might correspond to biologically significant differences in maternal and paternal influences on inheritance and development.…”

“…Retention of a transcriptionally poised chromatin state in gametes at developmental genes regulating all somatic lineages might underlie the gamete's ability to generate a zygote capable of producing each of these lineages. Others have proposed that this ability is driven by the activity of pluripotencyassociated transcription factors in the germ line (Leitch and Smith, 2013); poised chromatin might be an essential complement to such factors, especially during intervals when these pluripotency factors are not expressed in germ cells. In our model, genes that were poised in the germ cells would remain poised in the embryo during the first few cell divisions, possibly due to the influence of pluripotency factors.…”

Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors

“…Considering that pluripotency genes are reportedly protected from methylation throughout the male germline cycle (Leitch and Smith 2013), then ECs are still in the germline cycle, while derivative TEs and YSTs have exited from it, culminating with end-game methylation of the pluripotency circuit. The implication for other malignancies that may have passed through a similar pluripotent intermediate stage, but without a retained pluripotent state in the differentiated tumor mass, is that mCpH-pluri will likely be departed.…”