Our research is focused on understanding the fundamental molecular mechanisms by which genomes are remodeled to create a totipotent state and how this remodeling is coupled with transcriptional activity. Immediately following fertilization, the genome undergoes epigenetic reprogramming to allow for the transition from a specified germ cell to the pluripotent cells of the early embryo. During this stage, zygotic development is controlled by maternally contributed mRNAs and proteins, and transcriptional activation of the zygotic genome is delayed until hours after fertilization. This delayed transcriptional activation is a nearly universal phenomenon in all metazoans. Zygotic genome activation is tightly coordinated with the degradation of maternally provided mRNAs at the maternal-to-zygotic transition (MZT). Thus during this discrete developmental time point the transcriptional profile of the developing embryo undergoes a monumental reorganization.
In Drosophila the transcription factor Zelda is essential for activation of the zygotic genome and regulates transcription of hundreds of genes during the initial stages of development. Our research has shown that Zelda has the defining features of a pioneer transcription factor, which establishes regulatory elements that drive gene expression. Our ongoing studies are focused on understanding how Zelda remodels the zygotic genome to prepare the embryo for widespread transcriptional activation. Recently, we have identified a role for an additional pioneer-like transcription factor, GAGA factor, in working with Zelda to remodel the zygotic genome and activate transcription.
Zelda drives zygotic genome activation in Drosophila. Nuclearly localized Zelda binds to a set of related heptameric DNA elements early in embryonic development and poises thousands of genes for activation at the maternal-to-zygotic transition (Harrison et al. PLoS Genet 2011)
Harrison, M.M., Marsh, A.J., and C.A. Rushlow. (2023) Setting the stage for development: the maternal-to-zygotic transition in Drosophila. Genetics doi:10.1093/genetics/iyad142
Gaskill, M.M., Soluri, I.V., Brands, A.E., Book, A.P., Stadler, M.R., Vietor, K, Huang, H. S., Gibson, T.J., Mukherjee, A., Mir, M., Blythe, S.A., and Harrison, M.M. (2023) Localization of the Drosophila pioneer factor GAF to subnuclear foci is driven by DNA binding and required to silence satellite repeat expression. Dev Cell doi.org/10.1016/j.devcel.2023.06.010
Gaskill, M.M., Gibson, T.J., Larson, E.D. and Harrison, M.M. (2021) GAF is essential for zygotic genome activation and chromatin accessibility in the early Drosophila embryo. eLife doi.org/10.7554/eLife.66668
McDaniel, S.M., Gibson, T.J., Schulz, K.N., Fernandez Garcia, M., Nevil, M., Jain, S.U., Lewis, P.W., Zaret, K.S., and Harrison, M.M. (2019). Continued activity of the pioneer factor Zelda is required to drive zygotic genome activation. Mol Cell 74:185-195.
Hamm, D.C., Larson, E.D., Nevil, M. Marshall, K.E., and Bondra, E.R., and Harrison, M.M. (2018). A conserved maternal-specific repressive domain in Zelda revealed by Cas9-mediated mutagenesis in Drosophila melanogaster. PLoS Genet. 13:e1007120.
Schulz, K.N., Bondra, E.R., Moshe, A., Villalta, J.E., Lieb, J.D., Kaplan, T., McKay, D.J., and M.M. Harrison. (2015) Zelda is differentially required for chromatin accessibility, transcription-factor binding and gene in expression in the early Drosophila embryo. Genome Res. 25:1715-1726.
Hamm, D.C., Bondra, E.R., and M.M. Harrison. (2015) Transcriptional Activation is a Conserved Feature of the Early Embryonic Factor Zelda that Requires a Cluster of Four Zinc Fingers for DNA binding and Low-Complexity Activation Domain. J Biol Chem. 259:3508-3518.
Li, X.Y., Harrison, M.M., Villata, J.E., Kaplan, T., and M.B. Eisen. (2014) Establishment of regions of genomic activity during the Drosophila maternal to zyotic transition. eLife 3: doi10.7554.
Harrison, M.M., Li, X.Y., Kaplan, T., Botchan, M.R., and M.B. Eisen. (2011) Zelda Binding in the Early Drosophila melanogaster Embryo Marks Regions Subsequently Activated at the Maternal-to-Zygotic Transistion. PLoS Genet. 7:e1002266.
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.