Miguel Ramalho-Santos^{1, 2}

¹Lunenfeld-Tanenbaum Research Institute

²Department of Molecular Genetics, University of Toronto

Our lab is interested in the molecular mechanisms that regulate developmental timing in the early mammalian embryo and in pluripotent embryonic stem cells, and how such mechanisms are modulated by environmental inputs. We have pioneered studies of developmental hypertranscription, a phenomenon whereby cells globally elevate nascent transcription during growth stages of high biosynthetic demand. The converse of this hyperactive state is development pausing, or diapause, which we have found is a reversible state of “suspended animation” induced in mammalian blastocysts by nutrient deficits or direct inhibition of the mTOR kinase. In the context of these studies, we have uncovered a novel role for the transposon LINE1 as a regulator of chromatin organization that promotes developmental progression to the blastocyst stage. Our studies of environmental inputs into developmental epigenetics have led to the discovery that Vitamin C is a key co-factor for Tet enzymes, which mediate DNA demethylation in the early embryo and the embryonic germline. We are expanding these studies by dissecting the impact of a variety of environmental stressors during pregnancy on epigenetic states in embryonic cells, and determining how such perturbations can have long-term impacts in adulthood physiology and across generations.

We continue to focus on the molecular underpinnings of early development and how acutely attuned they are to environmental perturbations. Our fundamental research has important implications for the fields of reproductive health and developmental programming of adult-onset disease. In addition, we have found that the developmental processes that we study are frequently co-opted by adult cells. For example, we have recently shown that adult stem/progenitor cells across diverse organs enter akin to developmental hypertranscription during organ maintenance and regeneration. Conversely, we have found that adult cancer cells can enter a dormant state that is transcriptionally and functionally similar to embryonic diapause to survive chemotherapy and lead to cancer recurrence.