We are interested in understanding how the epigenome is established during human development and stem cell differentiation, and how epigenetic information changes over the life course of a person.
To research these topics, we use different types of stem cell (primarily human pluripotent stem cells), stem cell-based embryo models (blastoids and gastruloids), and donated human embryos, in combination with a variety of molecular and genetic approaches to investigate their epigenomes.
This research is important because establishing our epigenomes correctly during development is vital for establishing a healthy pregnancy, and has long lasting consequences on our health. We therefore need to know more about how it happens and why it sometimes goes wrong. Our work also provides new avenues for improving the epigenetic stability of human pluripotent stem cells, and our ability to drive their specialisation towards useful cell types, which are essential requirements to fulfill their promise in regenerative medicine.
Public dialogue is crucial for understanding societal views on human embryo research, and the complexity and sensitivity of this topic require special considerations of how such dialogues are facilitated. Here, we identify enablers of effective dialogue, which can improve the design and delivery of engagement exercises related to embryo research.
The human blastocyst contains the pluripotent epiblast from which human embryonic stem cells (hESCs) can be derived. ACTIVIN/NODAL signaling maintains expression of the transcription factor NANOG and in vitro propagation of hESCs. It is unknown whether this reflects a functional requirement for epiblast development in human embryos. Here, we characterized NODAL signaling activity during pre-implantation human development. We showed that NANOG is an early molecular marker restricted to the nascent human pluripotent epiblast and was initiated prior to the onset of NODAL signaling. We further demonstrated that expression of pluripotency-associated transcription factors NANOG, SOX2, OCT4, and KLF17 were maintained in the epiblast in the absence of NODAL signaling activity. Genome-wide transcriptional analysis showed that NODAL signaling inhibition did not decrease NANOG transcription or impact the wider pluripotency-associated gene regulatory network. These data suggest differences in the signaling requirements regulating pluripotency in the pre-implantation human epiblast compared with existing hESC culture.
Studies of mammalian development have advanced our understanding of the genetic, epigenetic, and cellular processes that orchestrate embryogenesis and have uncovered new insights into the unique aspects of human embryogenesis. Recent studies have now produced the first epigenetic maps of early human embryogenesis, stimulating new ideas about epigenetic reprogramming, cell fate control, and the potential mechanisms underpinning developmental plasticity in human embryos. In this review, we discuss these new insights into the epigenetic regulation of early human development and the importance of these processes for safeguarding development. We also highlight unanswered questions and key challenges that remain to be addressed.