The Pastor lab studies how transcription factors and epigenetic marks such as DNA methylation control early embryonic development. We use stem cell models such as human embryonic stem cells (hESCs), human induced pluripotent stem cells (hiPSCs) and human trophoblast stem cells (hTSCs) as models for understanding periods of human development which are otherwise hard to study. Core projects in our lab include:
1. Identifying and studying transcription factors important for placental development. The placenta has been called "the least understood organ". It arises early in development; the first cell fate decision is the split between the placental and non-placental lineage. The placenta grows rapidly, secretes hormones that drive the course of pregnancy, and mediates gas and nutrient exchange between mother and fetus. Defects of placentation can result in pregnancy complications such as miscarriage, stillbirth, pre-eclampsia, placental insufficiency, and placenta accreta.
Having evolved far more recently than other mammalian organs, interspecies difference in placental structures and gene regulation is especially striking, making human stem cell models an important tool. We are currently working to determine which transcription factors mediate specification of placenta, growth and self-renewal of placental stem cells, and differentiation to different placental lineages.
2. Understanding how DNA methylation is imparted during the peri-implantation period of development. DNA methylation is a critical epigenetic silencing mark. During the first week of human embryonic development, most DNA methylation is lost. Then, approximately coincident with embryonic implantation into the uterine wall, there is a mass wave of DNA methylation across the genome. The pattern of methylation established in early development is largely maintained throughout subsequent development. In other words, by the time your existence results in a positive pregnancy test, your epigenome is already shaped.
We seek to determine how DNA methyltransferases, the enzymes the produce DNA methylation, are themselves regulated during this critical window of development, and how the mass methylation of the genome is initiated and controlled.
3. Determining how imprinting regulates early embryonic development. As discussed above (2), most DNA methylation is lost during the first week of embryonic development and then regained upon implantation. However, certain regions called "imprinted regions", retain DNA methylation inherited from the sperm and egg. Imprinted genes are disproportionately likely to be important for early development, and dysregulation of imprinting is implicated in placental abnormality and cancer.