Functional and mechanistic characterization of Foxd3 during mouse peri-implantation transitions.
General Genetics and Functional Genome Biology
Final Report Abstract
The eggs and the sperm are formed from a unique type of progenitors called primordial germ cells (PGC). From the point of view of the survival of our own species, the correct formation of these germ cells is perhaps the most important cell differentiation process during embryonic development. In addition, failures in the formation of germ cells or in their subsequent differentiation into eggs or sperm can cause infertility in humans. However, despite the relevance of PGC, the molecular mechanisms that allow their correct formation are still largely unknown. In part, this is due to the fact that PGC are very scarce and transient, as they only exist during early stages of embryonic development, making their molecular characterization extremely difficult. To overcome these limitations, at least partly, in vitro differentiation systems have emerged according to which mouse or human embryonic stem cells can be efficiently differentiated into PGC. This allows PGC to be obtained in large numbers and without the need to use embryos. In this project, we have used this in vitro differentiation system to investigate the molecular mechanisms involved in the formation of PGC. Briefly, we uncovered that the epigenetic state of a set of regulatory sequences called enhancers is essential for the correct differentiation of PGC. More specifically, we showed that the presence of certain modifications in histones, the proteins that package DNA in our cells, are necessary for enhancers to activate the genes required during the formation of PGC. These findings may help improving protocols for generating eggs and sperm in vitro, which may offer a future solution to the growing problem of infertility in humans. The work derived from this project was recently published in the journal Nature Communications.
Publications
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Enhancer-associated H3K4 methylation safeguards in vitro germline competence. Nat Commun. 2021 Oct 1;12(1):5771
Bleckwehl T, Crispatzu G, Schaaf K, Respuela P, Bartusel M, Benson L, Clark SJ, Dorighi KM, Barral A, Laugsch M, van IJcken WFJ, Manzanares M, Wysocka J, Reik W, Rada-Iglesias A
