Transcriptional and epigenetic regulation of the trophoblast stem cell compartment
Only a few days after fertilization, at the blastocyst stage, an irreversible developmental decision is made that separates cells of the future placenta (so-called trophoblast cells) from those that will give rise to the embryo proper (Fig. 1). The emergence of trophoblast cells as the earliest cell type in development reflects their imminent importance for embryo implantation and nutrition throughout gestation. These first cell lineages also give rise to distinct types of stem cells that can be propagated indefinitely in culture, most notably embryonic (ES) and trophoblast (TS) stem cells (Fig. 1).
Fig 1. The first definitive cell lineage decision occurs at the blastocyst stage between the inner cell mass (ICM) and the outer trophectoderm (TE). The TE establishes the trophoblast cell lineage that exclusively contributes to formation of the placenta.Distinct types of stem cells can be derived from both cell lineages, embryonic stem (ES) cells from the ICM and trophoblast stem (TS) cell from the TE. These stem cells cannot normally inter-convert or “transdifferentiate”, such that their developmental potential is restricted to the embryo and placenta, respectively. This cell fate commitment is achieved by an epigenetic barrier that sets up lineage-specific transcriptional circuits. DNA methylation is a particularly important epigenetic modification in this context, which acts by targeting and repressing the transcription factor Elf5 in the embryonic lineage but not in the trophoblast lineage where Elf5 is hypomethylated and expressed.
Epigenetic Lineage barriersWe are interested in understanding how the first, very tight lineage barriers are established, and how they may be manipulated to instruct the developmental potency of stem cells. The basis of cell fate commitment lies in the establishment of a cellular memory that is achieved by epigenetic modifications and defines fate restriction of cell lineages and their derived stem cells. We are exploring epigenetic modifications that contribute to the stable maintenance of cell lineage identity in global epigenomic and proteomic approaches.
Transcriptional networks and their regulation that determine self-renewal and differentiation within the trophoblast lineageStem cell self-renewal depends on a variety of transcription factors that form defining and often self-reinforcing transcriptional circuits. In addition to exploring the epigenetic requirements of early embryo-derived stem cells, we are investigating the transcriptional networks within the trophoblast lineage genome-wide using state-of-the-art high-throughput sequencing approaches, and link these with the stem cell type-specific methylomes to delineate their epigenetic regulation (Fig. 2). We are also investigating how specific signaling pathways regulate these transcriptional networks.
As core member of the Centre for Trophoblast Research http://www.trophoblast.cam.ac.uk/
, we are extrapolating these insights into the human situation to gain insights into the regulation of earliest developmental processes that ensure normal progression of pregnancy. These approaches will advance our knowledge of early development and reproduction, as well as of the control of stem cell potency and differentiation with impact on their application in regenerative medicine.
Fig. 2 Transcription factor networks determine the establishment of the trophoblast lineage in early development and that dictate self-renewal and differentiation of trophoblast stem (TS) cells in vitro. Immunostaining shows the co-expression of two key factors, Tcfap2c (red) and Eomes (green) in a TS cell colony within a partially differentiated trophoblast population.