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.
Human pluripotent stem cells (hPSCs) are of fundamental relevance in regenerative medicine. Naïve hPSCs hold promise to overcome some of the limitations of conventional (primed) hPSCs, including recurrent epigenetic anomalies. Naïve-to-primed transition (capacitation) follows transcriptional dynamics of human embryonic epiblast and is necessary for somatic differentiation from naïve hPSCs. We found that capacitated hPSCs are transcriptionally closer to postimplantation epiblast than conventional hPSCs. This prompted us to comprehensively study epigenetic and related transcriptional changes during capacitation. Our results show that CpG islands, gene regulatory elements, and retrotransposons are hotspots of epigenetic dynamics during capacitation and indicate possible distinct roles of specific epigenetic modifications in gene expression control between naïve and primed hPSCs. Unexpectedly, PRC2 activity appeared to be dispensable for the capacitation. We find that capacitated hPSCs acquire an epigenetic state similar to conventional hPSCs. Significantly, however, the X chromosome erosion frequently observed in conventional female hPSCs is reversed by resetting and subsequent capacitation.
The totipotent embryo initiates transcription during zygotic or embryonic genome activation (EGA, ZGA). ZGA occurs at the 8-cell stage in humans and its failure leads to developmental arrest. Understanding the molecular pathways underlying ZGA and totipotency is essential to comprehend human development. Recently, human 8-cell-like cells (8CLCs) have been discovered in vitro that resemble the 8-cell embryo. 8CLCs exist among naive pluripotent stem cells and can be induced genetically or chemically. Their ZGA-like transcriptome, transposable element activation, 8-cell embryo-specific protein expression, and developmental properties make them an exceptional model system to study early embryonic cell-state transitions and human totipotency programs in vitro.
No abstract available