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During mammalian embryonic development, the trophectoderm and primitive endoderm give rise to extraembryonic tissues, while the epiblast differentiates into all somatic lineages and the germline. Remarkably, only a few classes of signaling pathways induce the differentiation of these progenitor cells into diverse lineages. Accordingly, the functional outcome of a particular signal depends on the developmental competence of the target cells. Thus, developmental competence can be defined as the ability of a cell to integrate intrinsic and extrinsic cues to execute a specific developmental program toward a specific cell fate. Downstream of signaling, there is the combinatorial activity of transcription factors and their cofactors, which is modulated by the chromatin state of the target cells. Here, we discuss the concept of developmental competence, and the factors that regulate this state with reference to the specification of mammalian primordial germ cells.

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.

Histone sind das Ziel von verschiedenen posttranslationalen chemischen Modifikationen, die für die Regulation der Genexpression eine Rolle spielen. Die Funktion der Histone jedoch konnte bislang nicht direkt in höheren Organismen untersucht werden, da es keine entsprechenden Histonmutanten gab. Dies lässt sich darauf zurückführen, dass die Histongene bei höheren Eukaryoten jeweils in hoher Kopienzahl und im Genom verteilt sind. Bei Drosophila melanogaster sind alle Histongene in einer distinkten Chromosomenregion, im sogenannten Histonkomplex, lokalisiert, der aus 23 sich wiederholenden Histongeneinheiten (His-GE) besteht, wobei jede Einheit für jeweils eine Kopie der Histongene codiert. Diese Genomorganisation ermöglichte es, den gesamten Histonkomplex zu deletieren und damit die erste definierte Histonnullmutation (HisC) in einem eukaryotischen Organismus herzustellen. HisC-mutante Embryonen, die über maternal eingelagerte Histon-mRNAs und Histonproteine verfügen, führen die ersten 14 embryonalen Zellzyklen aus. Danach sind die mutanten Zellen zwar noch in der Lage, die DNA-Replikation in der S-Phase 15 vollständig durchzuführen, arretieren dann aber im Zellzyklus. Die Ergebnisse lassen den Schluss zu, dass Histonneusynthese und DNA-Replikationsrate gekoppelte Prozesse sind, und dass es einen bislang unbekannten Mechanismus gibt, der während oder nach der DNA-Replikation die Nukleosomenassemblierung überwacht und gegebenenfalls einen Zellzyklusarrest bewirkt, der von der Repression der Phosphatase String abhängig ist. Die Ergebnisse zeigen auch, dass die HisC-Deletion durch transgene Histongene dosisabhängig komplementiert wird. Dieses Histondeletion/Transgen-System ermöglicht es, die Funktion von Histon-abhängigen Prozessen und die biologische Relevanz von Histonmodifikationen in einem multizellulären Organismus zu untersuchen und damit auch erstmalig die „Histoncode“-Hypothese kritisch zu testen., Histones are target of post-translational chemical modifications that modulate chromatin structure and control genome function. It was not possible, however, to directly assess the in vivo function of histones in higher eukaryotes, since corresponding histone mutants were not available. The lack of such histone mutants, and in particular a histone null mutant, is due to the reiteration and wide genomic distribution of histone genes in most of the higher organisms. In order to establish an experimental system that allows testing designed histone mutants, I made use of the unique histone gene organization in Drosophila melanogaster, where all histone genes are clustered at a single chromosomal site in the ‘histone complex’. Here I report the generation and characterization of a deletion that uncovers the histone complex, representing a histone null mutation (termed ‘HisC’). In HisC mutant embryos, the maternally derived histones are sufficient to drive the first 14 embryonic cell cycles. In the absence of zygotic histone expression, embryos fail to complete cell cycle 15 and die. The mutant cells are able to duplicate their DNA at very low rate in S phase 15 but they fail to enter the subsequent mitosis and arrest instead. The results suggest that histone supply determines the rate of S phase progression to ensure a balance between DNA replication and nucleosome assembly. In addition, the data imply a novel surveillance mechanism that is able to stall the cell cycle by repressing the expression of the phosphatase String when proper nucleosome assembly fails. Moreover, both cellular and embryonic lethality phenotypes could be rescued in a gene dose-dependent manner by transgenes carrying histone genes. This novel histone deletion/transgene system provides a unique tool to explore histone-based processes and to test the significance of histone modifications in terms of the proposed ‘histone code’ in a multicellular organism.