Our lab is interested in epigenetic gene regulation in mammalian development and in ageing. Global epigenetic reprogramming occurs at fertilisation and fundamentally remodels the epigenomes of sperm and egg. We are working to understand the mechanisms of reprogramming and also how it may be linked with zygotic genome activation, the sudden transcriptional springing to life of the genome in the early embryo.
Soon after implantation of the embryo in the maternal uterus there is a major programme of cell fate decisions which establishes the three primary germ layers, the ectoderm (which gives rise to brain and skin), the mesoderm (giving rise to muscle and heart), and the endoderm (which gives rise to the gut amongst other tissues).
These three lineages are the foundations of all organs in the adult body and we are interested in the transcriptional and epigenetic events that underlie their emergence from the undifferentiated epiblast. Finally, we are studying how the epigenome degrades during ageing potentially in a programmed fashion, and whether there are approaches by which this degradation can be slowed down or reversed.
During mouse gastrulation, extraembryonic mesoderm (ExEM) contributes to the extraembryonic yolk sac (YS) and allantois, both of which are essential for successful gestation. Although the genetic networks coordinating intra-embryonic mesodermal subtype specification are well studied, ExEM diversification remains poorly understood. Here, we identify that embryoid body (EB) in vitro differentiation generates distinct lineages of mesodermal cells, matching YS and allantois development. Combining in vitro and in vivo mouse models, we discover that Eomesodermin (Eomes) controls the formation of YS-fated ExEM but is dispensable for allantois formation. Furthermore, simultaneous disruption of Eomes and T impedes the specification of any YS or allantois mesoderm, indicating compensatory roles for T during allantois formation upon Eomes depletion. Our study highlights previously unrecognized functional and mechanistic diversity in ExEM diversification and endothelial development and introduces a tractable EB model to dissect the signaling pathways and transcriptional networks driving the formation of key extraembryonic tissues.
Early human trophoblast development has remained elusive due to the inaccessibility of the early conceptus. Non-human primate models recapitulate many features of human development and allow access to early postimplantation stages. Here, we tracked the pre- to postimplantation transition of the trophoblast lineage in superficially implanting marmoset embryos in vivo. We differentiated marmoset naive pluripotent stem cells into trophoblast stem cells (TSCs), which exhibited trophoblast-specific transcriptome, methylome, differentiation potential, and long-term self-renewal. Notably, human TSC culture conditions failed to support marmoset TSC derivation, instead inducing an extraembryonic mesoderm-like fate in marmoset cells. We show that combined MEK, TGF-β/NODAL, and histone deacetylase inhibition stabilizes a periimplantation trophoblast-like identity in marmoset TSCs. By contrast, these conditions differentiated human TSCs toward extravillous trophoblasts. Our work presents a paradigm to harness the evolutionary divergence in implantation strategies to elucidate human trophoblast development and invasion.
Ageing is the accumulation of changes and decline of function of organisms over time. The concept and biomarkers of biological age have been established, notably DNA methylation-based clocks. The emergence of single-cell DNA methylation profiling methods opens the possibility of studying the biological age of individual cells. Here, we generate a large single-cell DNA methylation and transcriptome dataset from mouse peripheral blood samples, spanning a broad range of ages. The number of genes expressed increases with age, but gene-specific changes are small. We next develop scEpiAge, a single-cell DNA methylation age predictor, which can accurately predict age in (very sparse) publicly available datasets, and also in single cells. DNA methylation age distribution is wider than technically expected, indicating epigenetic age heterogeneity and functional differences. Our work provides a foundation for single-cell and sparse data epigenetic age predictors, validates their functionality and highlights epigenetic heterogeneity during ageing.