The long-term goal of our lab is to understand the role that histone methylation plays in specifying cell fate, and to determine how defects in the regulation of histone methylation can give rise to human disease.
Our basic research paradigm is to use molecular biology and genetics to study the function of histone methylation in the C. elegans germline. We then test the mechanisms that we have uncovered, in mouse stem cell and developmental models. This allows us to determine how defects in these mechanisms can lead to human disease. We have shown, in C. elegans, that the histone demethylase LSD1 is required in the germline to reprogram H3K4me2 and prevent this epigenetic transcriptional memory from being inherited transgenerationally. We have also demonstrated that H3K4me2 demethylation in the germline is coupled to the acquisition of H3K9 methylation. We are currently investigating how this pathway affects the transgenerational inheritance of phenotypes in C. elegans. We are also investigating this pathway in the mice. We have shown that LSD1 plays a conserved role in maternal epigenetic reprogramming and we have investigated how defects in this reprogramming can lead to phenotypes that manifest after birth, including behavioral abnormalities. We have also demonstrated a role for LSD1 in the differentiation of multiple stem cell populations and we are investigating the function of LSD1 in iPS reprogramming. Finally, our studies in the mouse germline have led us to propose a role for this pathway in Alzheimer’s Disease and the related Frontotemporal Dementia. We are currently investigating this novel link further. In addition, we are pursuing the function of this pathway in the epigenetic maintenance of differentiated states.
