Developmental and stem cell biologists often assume that development is a process hardwired in the genome and insulated from environmental influence. However, a growing body of evidence shows that deficiencies in maternal diet or exposure to environmental toxins during gestation may affect developmental trajectories and program postnatal disease propensity in the progeny(Gluckman et al, Boekelheide et al, Bygren). The mechanisms that underlie the environmental modulation of developmental and stem cell biology remain largely unknown.
We discovered that the essential nutrient Vitamin C impacts the transcriptional and epigenetic state of ES cells in remarkable ways by acting as a specific co-factor for Tet enzymes and greatly enhancing DNA demethylation (Blaschke et al ). We are now using mouse models of Vitamin C deficiency to determine the effect of windows of withdrawal during gestation on epigenetic states in the embryo. Our results raise the possibility that dietary Vitamin C regulates the epigenetic state and function of the germline in vivo, potentially with transgenerational consequences. Our findings have implications in other stem cell systems where Tet enzymes are active, including the hematopoietic system and the brain. In addition, deficiencies in the activity of Tets have been causally linked to several types of cancer (e.g. Lian et al, Shih et al). This work highlights how sensitive the epigenetic state of pluripotent stem cells is to environmental factors, be it nutrition in vivo or media composition in vitro.
Moving forward on this avenue, our lab will explore how environmental stresses are sensed by pluripotent stem cells, and in particularly whether they induce the mutagenic activity of TEs. A conserved response to a variety of cellular stresses across living organisms is the de-repression of TEs (Fedoroff). Such stress response may be a mechanism for evolvability, by ensuring that novel genomic variants generated by TEs can undergo selection under a challenging environment. However, the downside of evolvability conferred by TEs at a species level may be genetic developmental programming of disease at the individual level. In particular, stresses during gestation may activate TEs that mutagenize the genome, creating mosaic individuals that are sensitized for adult-onset disease and may transmit new variants to the next generations. We are interested in using tools such as functional genomics and single-cell genome sequencing to understand the impact of stress-induced TEs on cellular heterogeneity during pluripotent stem cell differentiation and development.