Christine Rushlow

Transcriptional activation of the early Drosophila genome

Figure 1. Zelda protein is present in nuclei (green dots) from early on, accumulating in the next hour and persisting through nc14

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

Date of these PubMed search results: March 24 2020
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1. The Drosophila Pioneer Factor Zelda Modulates the Nuclear Microenvironment of a Dorsal Target Enhancer to Potentiate Transcriptional Output.
   Curr Biol (2019 Apr 22) PMC6702943 free full-text archive
   Yamada S, Whitney PH, Huang SK, Eck EC, Garcia HG, Rushlow CA
2. Metabolic Regulation of Developmental Cell Cycles and Zygotic Transcription.
   Curr Biol (2019 Apr 1) PMC6501590 free full-text archive
   Djabrayan NJ, Smits CM, Krajnc M, Stern T, Yamada S, Lemon WC, Keller PJ, Rushlow CA, Shvartsman SY
3. BMP Signaling Determines Body Size via Transcriptional Regulation of Collagen Genes in Caenorhabditis elegans.
   Genetics (2018 Dec) PMC6283163 free full-text archive
   Madaan U, Yzeiraj E, Meade M, Clark JF, Rushlow CA, Savage‑Dunn C
4. A Systematic Ensemble Approach to Thermodynamic Modeling of Gene Expression from Sequence Data.
   Cell Syst (2015 Dec 23) PMC5094195 free full-text archive
   Samee MA, Lim B, Samper N, Lu H, Rushlow CA, Jimenez G, Shvartsman SY, Sinha S
5. Zelda overcomes the high intrinsic nucleosome barrier at enhancers during Drosophila zygotic genome activation.
   Genome Res (2015 Nov) PMC4617966 free full-text archive
   Sun Y, Nien CY, Chen K, Liu HY, Johnston J, Zeitlinger J, Rushlow C
6. Zelda potentiates morphogen activity by increasing chromatin accessibility.
   Curr Biol (2014 Jun 16) PMC4075064 free full-text archive
   Foo SM, Sun Y, Lim B, Ziukaite R, O'Brien K, Nien CY, Kirov N, Shvartsman SY, Rushlow CA
7. Co-activation of microRNAs by Zelda is essential for early Drosophila development.
   Development (2014 May) PMC4011091 free full-text archive
   Fu S, Nien CY, Liang HL, Rushlow C
8. Kinetics of gene derepression by ERK signaling.
   Proc Natl Acad Sci U S A (2013 Jun 18) PMC3690897 free full-text archive
   Lim B, Samper N, Lu H, Rushlow C, Jimenez G, Shvartsman SY
9. Temporal dynamics, spatial range, and transcriptional interpretation of the Dorsal morphogen gradient.
   Curr Opin Genet Dev (2012 Dec) PMID: 22981910
   Rushlow CA, Shvartsman SY
10. Pausing on the path to robustness.
    Dev Cell (2012 May 15) PMID: 22595664
    Siegal ML, Rushlow C
11. Response to the BMP gradient requires highly combinatorial inputs from multiple patterning systems in the Drosophila embryo.
    Development (2012 Jun) PMC3347688 free full-text archive
    Liang HL, Xu M, Chuang YC, Rushlow C
12. Pattern formation by graded and uniform signals in the early Drosophila embryo.
    Biophys J (2012 Feb 8) PMC3274790 free full-text archive
    Kanodia JS, Liang HL, Kim Y, Lim B, Zhan M, Lu H, Rushlow CA, Shvartsman SY
13. Temporal coordination of gene networks by Zelda in the early Drosophila embryo.
    PLoS Genet (2011 Oct) PMC3197689 free full-text archive
    Nien CY, Liang HL, Butcher S, Sun Y, Fu S, Gocha T, Kirov N, Manak JR, Rushlow C
14. Combinatorial activation and concentration-dependent repression of the Drosophila even skipped stripe 3+7 enhancer.
    Development (2011 Oct) PMC3171227 free full-text archive
    Struffi P, Corado M, Kaplan L, Yu D, Rushlow C, Small S
15. The zinc-finger protein Zelda is a key activator of the early zygotic genome in Drosophila.
    Nature (2008 Nov 20) PMC2597674 free full-text archive
    Liang HL, Nien CY, Liu HY, Metzstein MM, Kirov N, Rushlow C
16. Multiple modular promoter elements drive graded brinker expression in response to the Dpp morphogen gradient.
    Development (2008 Jun) PMC3027062 free full-text archive
    Yao LC, Phin S, Cho J, Rushlow C, Arora K, Warrior R
17. Threshold response of C15 to the Dpp gradient in Drosophila is established by the cumulative effect of Smad and Zen activators and negative cues.
    Development (2006 Dec) PMID: 17092951
    Lin MC, Park J, Kirov N, Rushlow C
18. Peak levels of BMP in the Drosophila embryo control target genes by a feed-forward mechanism.
    Development (2005 Apr) PMID: 15728670
    Xu M, Kirov N, Rushlow C
19. Dorsoventral patterning: a serpin pinned down at last.
    Curr Biol (2004 Jan 6) PMID: 14711428
    Rushlow C
20. Transcriptional regulation of the Drosophila gene zen by competing Smad and Brinker inputs.
    Genes Dev (2001 Feb 1) PMC312624 free full-text archive
    Rushlow C, Colosimo PF, Lin MC, Xu M, Kirov N
21. The role of brinker in mediating the graded response to Dpp in early Drosophila embryos.
    Development (1999 Aug) PMID: 10393112
    Jazwinska A, Rushlow C, Roth S
22. The Drosophila gene brinker reveals a novel mechanism of Dpp target gene regulation.
    Cell (1999 Feb 19) PMID: 10052458
    Jazwinska A, Kirov N, Wieschaus E, Roth S, Rushlow C
23. Isolation and characterization of a new gene encoding a member of the HIRA family of proteins from Drosophila melanogaster.
    Gene (1998 Jun 8) PMID: 9611274
    Kirov N, Shtilbans A, Rushlow C
24. The transcriptional corepressor DSP1 inhibits activated transcription by disrupting TFIIA-TBP complex formation.
    EMBO J (1996 Dec 16) PMC452533 free full-text archive
    Kirov NC, Lieberman PM, Rushlow C
25. A group of genes required for maintenance of the amnioserosa tissue in Drosophila.
    Development (1996 May) PMID: 8625823
    Frank LH, Rushlow C
26. The Drosophila dorsal morphogen represses the tolloid gene by interacting with a silencer element.
    Mol Cell Biol (1994 Jan) PMC358420 free full-text archive
    Kirov N, Childs S, O'Connor M, Rushlow C
27. Conversion of a silencer into an enhancer: evidence for a co-repressor in dorsal-mediated repression in Drosophila.
    EMBO J (1993 Aug) PMC413585 free full-text archive
    Kirov N, Zhelnin L, Shah J, Rushlow C
28. Individual dorsal morphogen binding sites mediate activation and repression in the Drosophila embryo.
    EMBO J (1992 Aug) PMC556799 free full-text archive
    Jiang J, Rushlow CA, Zhou Q, Small S, Levine M
29. The rel family of proteins.
    Bioessays (1992 Feb) PMID: 1533515
    Rushlow C, Warrior R
30. The dorsal morphogen is a sequence-specific DNA-binding protein that interacts with a long-range repression element in Drosophila.
    Cell (1991 Jan 25) PMID: 1988156
    Ip YT, Kraut R, Levine M, Rushlow CA
31. Dorsal ventral polarity and pattern formation in the Drosophila embryo.
    Semin Cell Biol (1990 Jun) PMID: 2103885
    Rushlow C, Arora K
32. Role of the zerknullt gene in dorsal-ventral pattern formation in Drosophila.
    Adv Genet (1990) PMID: 2112301
    Rushlow C, Levine M
33. The graded distribution of the dorsal morphogen is initiated by selective nuclear transport in Drosophila.
    Cell (1989 Dec 22) PMID: 2598265
    Rushlow CA, Han K, Manley JL, Levine M
34. The Drosophila hairy protein acts in both segmentation and bristle patterning and shows homology to N-myc.
    EMBO J (1989 Oct) PMC401388 free full-text archive
    Rushlow CA, Hogan A, Pinchin SM, Howe KM, Lardelli M, Ish‑Horowicz D
35. Combinatorial expression of a ftz-zen fusion promoter suggests the occurrence of cis interactions between genes of the ANT-C.
    EMBO J (1988 Nov) PMC454848 free full-text archive
    Rushlow C, Levine M
36. Region-specific alleles of the Drosophila segmentation gene hairy.
    Genes Dev (1988 Aug) PMID: 3169547
    Howard K, Ingham P, Rushlow C
37. Maternal regulation of zerknullt: a homoeobox gene controlling differentiation of dorsal tissues in Drosophila.
    Nature (1987 Dec 10-16) PMID: 2891036
    Rushlow C, Frasch M, Doyle H, Levine M
38. Molecular characterization of the zerknullt region of the Antennapedia gene complex in Drosophila.
    Genes Dev (1987 Dec) PMID: 2892759
    Rushlow C, Doyle H, Hoey T, Levine M
39. Characterization and localization of the even-skipped protein of Drosophila.
    EMBO J (1987 Mar) PMC553460 free full-text archive
    Frasch M, Hoey T, Rushlow C, Doyle H, Levine M
40. Cross-regulatory interactions among pair-rule genes in Drosophila.
    Science (1986 Aug 29) PMID: 3755551
    Harding K, Rushlow C, Doyle HJ, Hoey T, Levine M
41. Tissue-specific and pretranslational character of variants of the rosy locus control element in Drosophila melanogaster.
    Genetics (1984 Dec) PMC1224276 free full-text archive
    Clark SH, Daniels S, Rushlow CA, Hilliker AJ, Chovnick A
42. Heterochromatic position effect at the rosy locus of Drosophila melanogaster: cytological, genetic and biochemical characterization.
    Genetics (1984 Nov) PMC1202427 free full-text archive
    Rushlow CA, Chovnick A
43. Studies on the mechanism of heterochromatic position effect at the rosy locus of Drosophila melanogaster.
    Genetics (1984 Nov) PMC1202428 free full-text archive
    Rushlow CA, Bender W, Chovnick A
44. Structural and functional organization of a gene in Drosophila melanogaster.
    Basic Life Sci (1980) PMID: 6779795
    Chovnick A, McCarron M, Clark SH, Hilliker AJ, Rushlow CA