The Pastor lab studies how transcription factors and epigenetic marks such as DNA methylation control early embryonic development. We use human embryonic stem cells (hESCs) and human trophoblast stem cells (hTSCs) as models for understanding periods of human development which are otherwise hard to study, as well as mouse models and clinical samples. We make extensive use of sequencing technology to study transcriptional regulation and we perform our own bioinformatic analysis. Core projects in our lab include:
1. Understanding DNA methylation. 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 are studying how DNA methylation is targeted during the peri-implantation period and why different cell lineages emerge with different patterns of DNA methylation. We are also studying how loss of DNA methylation causes cell death and perturbs development.
2. 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. We are also studying why DNA methylation patterns are so different in placental and embryonic lineage.
3. Determining the molecular and developmental roles of ZMYM2. ZMYM2 is a transcriptional repressor, and loss of one copy of ZMYM2 results in neurological, musculoskeletal, and kidney abnormalities in human patients. We discovered that ZMYM2 is a critical factor in guiding DNA methylation in early development. Our work further indicates that ZMYM2 is likely to be important for transcriptional silencing in many other developmental contexts and that it functions as a corepressor for many chromatin-bound proteins. We are studying both the molecular and developmental roles of ZMYM2 in order to understand how it works and why its loss results in pathological phenotypes in humans.