Melissa M. Harrison
6204B Biochemical Sciences Building
440 Henry Mall, Madison, WI 53706
• A.B. 1998, Harvard University
• Ph.D. 2006, M.I.T. (H.R. Horvitz)
• Postdoctoral Fellow 2006-2011, University of California, Berkeley (M.R. Botchan and T.W. Cline)
Honors & Awards
• Howard Hughes Predoctoral Fellow, 1999-2004
• American Cancer Society Postdoctoral Fellow, 2007-2010
• Wisconsin Partnership Program New Investigator Award 2014
• March of Dimes Basil O’Connor Starter Scholar Research Award 2014
• Vallee Foundation Young Investigator Award in Biomedical Science 2016
Development and differentiation are driven by coordinated changes in gene expression. Early 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. 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. The zygotic genome remains transcriptionally quiescent during these initial stages. Only at later cell cycles is widespread zygotic transcription initiated. This 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.
While most of the genome is silenced prior to the MZT, a small subset of genes is expressed. These genes control fundamental processes essential for the future development of the organism and allow for progression through the MZT. Despite the fact that these developmental events are common from plants to vertebrates, little is currently known about the factors that regulate zygotic genome activation at the MZT or the mechanisms that allow for the selective transcription of a handful of genes at earlier time points. An understanding of these mechanisms will provide insights into how the genomes of pluripotent cells in general, including embryonic, cancer and induced-pluripotent stem cells, maintain their broad developmental potential while being poised to differentiate.
We use Drosophila melanogaster to study these phenomena using a wide variety of tools including biochemistry, genetics, molecular biology, genomics, and cell biology. Broadly, we are seeking to understand three outstanding questions: (1) why most of the genome is not transcribed until many nuclear divisions after fertilization, (2) how a small number of genes are expressed when the remainder of the genome is not, and (3) what triggers the widespread activation of the zygotic genome at the MZT.
Publications of Note
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• Bier, E., Harrison, M.M., O’Connor-Giles, K.M., and J. Wildonger. (2018) Advances in Engineering the Fly Genome with the CRISPR-Cas System. Genetics 208: 1-18.
• Hamm, D.C., Larson, E.D., Nevil, M.N., Marshall, K., Bondra, E.R., and M.M. Harrison. (2017) A conserved maternal-specific repressive domain in Zelda revealed by Cas9-mediated mutagenesis in Drosophila melanogaster. PLoS Genet 13:e1007120.
• Janssens, D.H., Hamm, D.C., Xiao, Q., Anhezini De Araujo, L., Siller, K.H., Siegrist, S.E., Harrison, M.M., and C.Y. Lee. (2017) A novel Hdac1/Rpd3-poised circuit balances continual self-renewal and rapid restriction of developmental potential during asymmetric stem cell division. Dev Cell 40: 367-380.
• Nevil, M., Bondra, E.R., Schulz, K.N., Kaplay, T., and M.M. Harrison. (2017) Genome-wide analysis of the conserved transcription factor Grainy head reveals stable binding to target genes during development. Genetics 205: 605-620.
• Schulz, K.N., Bondra, E.R., Villalta, J.E., Lieb, J.D., Kaplan, T., McKay, D.J., and M.M. Harrison. (2015) Zelda is differentially required for chromatin acccessibility, transcription-factor biding and gene expression in the early Drosophila embryo. Genome Res 25: 1715-1726.
• Harrison, M.M. and M.B. Eisen. (2015) Transcriptional activaiton of the zygotic genome in Drosophila. Curr Top Dev Biol. 113: 85-112.
• Hamm, D.C., Bondra, E.R., M.M. Harrison. (2015) Transcirptional activation is a conserved feature of the early embryonic factor Zelda that requires a cluster of four zinc fingers for DNA binding and a low-complexity activation domain. J Biol Chem. 290: 3508-3518.
• Harrison, M.M., Jenkins, B.V., O’Connor-Giles, K.M. and J. WIldonger. (2014) A CRISPR view of development. Genes Dev. 28: 1859-1872.
• Gratz, S.J., Cummings, A.M., Nguyen, J.N., Hamm, D.C., Donohue, L.K., Harrison, M.M.*, Wildonger, J.* and K.M. O’Connor-Giles*. (2013) Genome engineering of Drosophila with the CRISPR RNA-guided Cas9-nuclease. Genetics. 194:1029-1035. (* denotes co-corresponding authors)
• 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 Transition. PLoS Genet. 7:e1002266. (* denotes equal contributions)