Christine A. Rushlow
Professor of Biology; Director, Masters Program
Ph.D. 1983 (genetics), B.A. 1977 (biology/chemistry), Connecticut.
|New York University|
|Department of Biology|
|1009 Silver Center|
|100 Washington Square East|
|New York, NY 10003-6688|
Transcriptional activation of the early Drosophila genome
The broad goal of my research program is to understand the molecular mechanisms that control early embryonic development. We use genetic, biochemical, and genomic approaches to study gene regulatory networks in the early Drosophila embryo. Initially the embryo relies on maternally deposited gene products to begin developing, and the transition to reliance on its own zygotic-gene activity is called the maternal-to-zygotic transition (MZT). The MZT represents a major cellular reprogramming event whereby thousands of maternal RNAs are degraded and hundreds of new zygotic RNAs are transcribed during the time between egg fertilization and blastoderm formation. Recently we discovered a key transcriptional regulator called Zelda, which plays a key role in this reprogramming event. Our goal is to understand how Zelda mediates the rapid and robust activation of the zygotic genome and how it works together with the other key transcription factors to prepare the embryo for major developmental processes such as gastrulation and tissue differentiation.
Currently, the major project in the lab aims to understand how Zelda functions at the mechanistic level. Zelda is a zinc-finger transcription factor, and binds to CAGGTAG and related sites (Liang et al., 2008). Interestingly, our genome-wide binding analysis (ChIP-chip/seq) showed that Zelda binds to known enhancers in the early embryo to such an extent that Zelda binding is a predictive indicator of the location of an enhancer (Nien et al., 2012). Zelda is the major hub in the early gene network (Liang et al., 2008; Nien et al., 2011). Zelda binds enhancers well before the gene is activated (Harrision et al., 2012; Nien et al., 2010), suggesting that Zelda might act as a pioneer factor, a special class of transcription factors that bind target sites in chromatin, allowing other factors access to enhancers (reviewed in Zaret and Carroll, 2011). In this way, Zelda may potentiate the activity of other transcription factors such as the patterning morphogens, an exciting hypothesis that points to the significance of Zelda function in embryonic patterning. We believe that Zelda works together with morphogens, and though we do not yet know how they interact, one fact is clear - that without Zelda, morphogens cannot function to their full potential, particularly when at low concentrations, and target genes are not activated at the right time and in the right place. Mechanistically, Zelda may act as a beacon on chromatin for other transcription factors. Without Zelda, these factors may not position correctly, and redistribute to other regions of the genome. In collaboration with the Zeitlinger lab at Stowers Institute, we are examining the chromatin landscape in wild type and zelda mutant embryos to determine how Zelda cooperates with other key regulators during the MZT.
A second Zelda project stems from the observation that Zelda is expressed in older embryos and larva, specifically in imaginal discs and the brain. For example in the eye disc and optic lobe of the brain, Zelda is expressed in the undifferentiated cells and is down-regulated upon differentiation. In the opitc lobe neuroepithelium, which comprises stem cells that give rise to neuroblasts/neurons, loss of Zelda causes premature differentiation. We propose that Zelda establishes the neural stem cell gene network, which prepares cells for the neuropeithelial to neuroblast transition.
The projects in the my lab require the use of several types of approaches from manipulating genes and transgenes and observing the output phenotypes, to systems/genome-wide studies that require bioinformatic analysis. We also collaborate with systems biologist Stas Shvartsman, who models Zelda interactions with the patterning morphogens. Together these approaches will allow an understanding of how global factors like Zelda interact with key regulators to control robust expression of the early zygotic genome.
I teach the undergraduate Genetics course. I participate in team-taught graduate lecture courses: Biocore I and II (the graduate core classes), and Developmental Genetics. I also run a graduate seminar, Current Topics in Genetics. In addition, I mentor several undergraduate students for their independent studies in the lab and their honors theses, as well as several Master's students for their Lab in Molecular Biology courses and Master's theses.
I received my Ph.D. from the University of Connecticut in 1983. My thesis mentor was Dr. Arthur Chovnick, a well known geneticist who studied gene organization in Drosophila. I moved to the laboratory of Dr. David Ish-Horowicz at the Imperial Cancer Research Fund in London, England to study developmental biology. I was particularly interested in the problem of cell fate determination. In 1986, I moved to Dr. Michael Levine's laboratory at Columbia University to study the problem of how morphogen gradients control cell fate. We discovered that the dorsal morphogen gradient is created by the mechanism of regulated nuclear transport.
In 1991 I started my own lab at the Roche Institute of Molecular Biology in New Jersey where I showed how the dorsal morphogen acts as a transcriptional repressor to control target gene expression. In 1995 I joined the faculty of New York University as an associate professor and was tenured in 1999. We have been studying how Dpp functions as a morphogen and how it differs from the classical morphogens Dorsal and Bicoid. We showed that feed forward motifs predominate in how Dpp regulates downstream target genes rather than the differential binding affinity mechanism.
Genetics Society of America, American Association for the Advancement of Science.
Whitehead Fellowship for Junior Faculty in Biological Sciences, 1996; American Cancer Society Research Grant NP600, July 1987-1991; American Cancer Society Postdoctoral Fellowship, November 1983-November 1985; PHS Genetics Training Grant, September 1978-September 1981.