Our work focuses on how transcription factors specify cell state/fate decisions, and how mechanisms responsible for these decisions control regeneration and may contribute to disease or be harnessed for regenerative therapies. Our model systems generally employ stem cells, both in vitro and in vivo.
Regulation of satellite cell quiescence and self-renewal. Skeletal muscle has tremendous capacity for regeneration after injury, but does not normally experience significant turnover. Satellite cells, the stem cells for skeletal muscle, are therefore quiescent. We are investigating mechanisms of regulation that govern quiescence and self-renewal of satellite cells, with a long-term goal of applying these to cell therapies for muscle diseases.
DUX4 and FSHD. The genetic disease facioscapulohumeral muscular dystrophy is caused by mutations leading to inappropriate expression of the double homeodomain transcription factor, DUX4. We are investigating the molecular mechanisms by which DUX4 recognizes DNA, alters chromatin and activates transcription, and are actively engaged in a program to discover and develop small molecule inhibitors of DUX4 for the treatment of FSHD. We have also developed an animal model for FSHD based on regulated, titratable expression of DUX4 in skeletal muscle.
DUX4 and childhood leukemia. Translocations that insert DUX4 into the IgH locus cause B cell leukemia. We are investigating the molecular mechanism underlying the oncogenic activity of DUX4-IGH fusion proteins.
Genome editing and genetic correction. We have developed induced pluripotent stem cell lines from individuals with FSHD and are engaged in genetic correction of the FSHD locus. Mutations that cause FSHD typically delete hundreds of kb of DNA, therefore approaches to genetic correction are non-conventional.
Mesoderm specification and patterning. The transcription factor Mesp1 has been thought of as a cardiac master regulator, however we have shown that Mesp1 can promote the differentiation of lineages other than heart, including skeletal muscle and blood, and that Mesp1-cre marks these other lineages during murine embryogenesis. We are currently investigating mechanisms of MESP1 action in the specification and patterning of mesoderm from human pluripotent stem cells with a view towards better understanding the mechanisms mesodermal fate specification in the human system, and the production of skeletal and cardiac myocytes in vitro.