Development and differentiation are driven by coordinated changes in gene expression. These changes in expression are controlled by transcription factors that bind to the genome and activate gene expression. While nucleosomes limit the ability of transcription factors to bind to the genome, specialized pioneer transcription factors have unique properties that allow them to bind DNA in the context of nucleosomes, define regulatory elements and facilitate the subsequent binding of additional factors that determine gene expression. These properties allow pioneer factors to act at the top of gene regulatory networks and control developmental transitions. We study conserved developmental transitions controlled by pioneer transcription factors to determine the fundamental molecular mechanisms by which these unique factors control widespread changes in gene expression and, conversely, how developmental context influences pioneer-factor binding and activity. Current research is focused on the conserved pioneer factor Grainy head that drives epithelial cell fate in a wide range of organisms and is mutated in numerous human cancers. In addition, we study the role of the pioneer factor Zelda in activating the zygotic genome but also in promoting the undifferentiated fate in neural stem cells in the Drosophila larva.
Larson, E.D., Komori, H., Gibson, T.J., Ostgaard, C.M., Hamm, D.C., Schnell, J.M., Lee, C-Y, and Harrison, M. M. (2021) Cell-type-specific chromatin occupancy by the pioneer factor Zelda drives key developmental transitions in Drosophila. Nat Comm. doi.org/10.1038/s41467-021-27506-y
Larson, E.D., Marsh, A.J., and Harrison, M. M. (2021) Pioneering the developmental frontier. Mol Cell 81: 1640-1650.
Nevil, M., Gibson, T.J., Bartolutti, C., Ayengar, A., and Harrison, M.M. (2020). Establishment of chromatin accessibility by the conserved transcription factor Grainy head is developmentally regulated. Development. 147:dev185009.
Reese, R.M., Harrison, M.M., and Alarid, E.T. (2019). Grainyhead-like protein 2: The emerging role in hormone-dependent cancers and epigenetics. Endocrinology 160: 1275-1288.
Nevil, M., Bondra, E. R., Schulz, K. N., Kaplan, T., and Harrison, M. M. (2017) Stable Binding of the Conserved Transcription Factor Grainy Head to Its Target Genes Throughout Drosophila melanogaster Development. Genetics. 205:605-620.
Harrison, M.M., Botchan, M.R. and T.W. Cline. (2010) Grainyhead and Zelda compete for binding to the promoters of the earliest-expressed Drosophila genes. Dev Biol. 345: 248-255.