Epigenetic Regulation of Development
and Stem Cell Differentiation
Epigenetic processes are at the interface between gene regulation and the environment, such that external influences can have a major and potentially long-term impact on gene expression. New studies are making strong links between alterations to epigenetic regulation during development and diseases of gestation and adult life.
To better understand these processes, our research group investigates how the epigenome is modulated during early mammalian development and stem cell differentiation. In particular, we focus on understanding how chromatin-modifying proteins interact with other critical processes during development, including signalling pathways and key transcription factors.
This research will provide crucial insight into how distinct cell types are formed in the embryo and will uncover new and safer ways to use stem cells for regenerative medicine. Our findings also have broad impact on understanding environmental influences on the epigenome, which has major implications for diet and other external factors during pregnancy.
Interactions between Polycomb and Signalling Pathways
Polycomb-group (PcG) proteins are critical regulators of transcriptional state during cell differentiation, yet how they are linked to the major cell signalling pathways that control early development remains poorly understood. Interactions between epigenetic and signalling pathways have not been investigated during early lineage differentiation, but strong functional evidence for this mode of epigenetic regulation exists in other mammalian cell types. These interactions typically lead to phosphorylation of PcG proteins, loss of repressive histone marks at promoter regions and alteration of transcriptional activity and cell behaviour. Together, these results demonstrate that intracellular signalling pathways can relay growth factor responses to regulate chromatin function.
The overall aim for our research group is to investigate interactions between PcG proteins and signaling pathways during cell fate decisions in the mammalian embryo and during stem cell differentiation (Figure 1). We use a variety of cellular and genetic manipulation techniques in stem cells and embryos to interrogate functional requirements for epigenetic and signaling pathways during development. We also use biochemical approaches to uncover the critical protein interactions that mediate these key processes.
Determining the epigenetic and signalling contributions to cell regulation is essential for unraveling how lineage specification is controlled. This is important for understanding the formation of distinct cell types in the mammalian embryo and for uncovering better ways to use stem cells for regenerative medicine.
Figure 1
Generation of the major cell lineages during gastrulation in the embryo and stem cell differentiation depends on interactions between epigenetic and signalling pathways. Our research group uniquely combines small-scale examination of embryo tissues, together with large-scale analysis of stem cells in culture, to understand the mechanisms that regulate cell differentiation. These multiple approaches allow us to maximise the benefits of each cellular system.
Epigenetic analysis of early embryo lineages
We are also interested in investigating the establishment and maintenance of the earliest cell lineages that are formed during embryogenesis. This research has major implications for cell fate decisions in developmental and stem cell biology. To begin to examine these questions, we have applied a large-scale proteomic approach to determine the cell-surface proteome of all embryo-derived stem cell lines. These results identified novel pathways that regulate lineage specification, and enabled the isolation of specific cell types during stem cell differentiation and reprogramming, and also directly from early mouse embryos (Figure 2). We will now use this technique, in combination with epigenomic and genomic approaches, to investigate the mechanisms that regulate cell fate decisions in the early mammalian embryo.
Figure 2 (Click to enlarge)
We have identified proteins that distinguish and visualise the three early cell lineages of the mouse embryo, shown here in blue, green and red. We now use antibodies raised against these proteins, in combination with flow cytometry, to prospectively isolate and functionally characterise each cell type directly from the embryo.
Updated 31 October, 2011