Abstract
During embryonic development, the foundation of the germline is laid by the specification of primordial germ cells (PGCs) from the postimplantation epiblast via bone morphogenetic protein (BMP) and WNT signalling. While the majority of epiblast cells undergo differentiation towards somatic cell lineages, PGCs initiate a unique cellular programme driven by the cooperation of the transcription factors BLIMP1, PRDM14 and AP2γ. These factors synergistically suppress the ongoing somatic differentiation and drive the re-expression of pluripotency and germ cell-specific genes accompanied by global epigenetic changes. However, an unresolved question is how postimplantation epiblast cells acquire the developmental competence for the PGC fate downstream of BMP/WNT signalling. One emerging concept is that transcriptional enhancers might play a central role in the establishment of developmental competence and the execution of cell fate determination. Here, we discuss recent advances on the specification and reprogramming of PGCs thereby highlighting the concept of enhancer function.
Highlights
Primordial germ cells (PGCs), the precursors of the gametes, represent a cell lineage with unique properties
ChIPseq studies for a number of transcription factors in embryonic stem (ES) cells revealed that the Bone morphogenetic protein (BMP) target SMAD1 together with OCT4, SOX2, NANOG and STAT3 co-bind loci that are mainly in intergenic regions, where enhancers reside, to drive ES-specific gene expression [31]
These factors in combination set up the initial condition required for reprogramming of PGCs, each one of them is involved in other processes and expressed in distinct tissues: BLIMP1 has been well characterized in the functional differentiation of B and T lymphocytes and other haematopoietic lineages as well as in the epidermis, with various different functions during development [59,60,61,62]; PRDM14 is required for maintaining naive pluripotency in ES cells by repressing fibroblast growth factor (FGF) signalling and DNA methylation [63,64]; AP2g is involved in the development of extraembryonic tissues among others [65]
Summary
Primordial germ cells (PGCs), the precursors of the gametes, represent a cell lineage with unique properties. Factors drive transcriptional changes and epigenetic remodelling in part by inducing the re-expression of pluripotency genes and repressing the DNA methylation machinery, accompanied by genome-wide DNA demethylation, X chromosome reactivation, erasure of imprints and dynamic changes in histone modification signatures [9,10,11,12,13,14] During this reprogramming event, PGCs proliferate and migrate towards the genital ridges, which they colonize by E10.5. At the time of PGC specification, postimplantation epiblast cells exhibit a state of primed pluripotency; they express some pluripotency-associated genes together with lineage commitment genes. These cells show signs of differentiation such as DNA methylation and an inactive X chromosome (in female embryos) [15,16,17,18,19]. We will discuss the specification and reprogramming of PGCs and, in particular, the principles of enhancer function with examples from different systems
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