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A clear revelation of the post-genome era is that vastly different organisms share a majority of genes in common. The regulation of these genes—when and where and at what levels they are expressed—is likely to account for the wide spectrum of animal forms observed in nature. Each gene in the genome is controlled by one to several modular stretches of DNA sequences called cis-regulatory DNAs. Predicting which DNA sequences function as cis-regulatory DNAs is now one of the greatest challenges of the post-genomics era.
As a graduate student I developed methods to identify cis-regulatory DNAs on a genome-wide scale (see www.opengenomics.org). Over the course of this work I identified several novel cis-regulatory DNAs targeted by the Drosophila transcription factor Dorsal. Dorsal is a member of the vertebrate NF-kappa B family of transcription factors, which in mammals plays a central role in mediating both acquired and innate immune responses. In flies Dorsal plays an additional role: it not only mediates innate immune responses, but also plays a central role in patterning the dorsal-ventral axis of the early fly embryo. Since the immune function of Dorsal is shared by both mammals and flies, the immune function is believed to be the basal function of Dorsal; whereas the role of Dorsal in embryonic patterning is believed to be a derived function.
To understand how the Dorsal transcription factor became co-opted from its role in innate immunity to a play a central role in dorsal-ventral patterning, it is necessary to track the evolution of Dorsal cis-regulatory targets. Currently there are several insect genomes available for this endeavor including the genomes of D. pseudoobscura, Anopheles gambiae, and Apis mellifera. However, without studying a sister group to the insect lineages, these genomes may be of limited use. Thus, to “fill the gap” in our understanding of Dorsal cis-regulatory targets, I am currently cloning the homologs of Dorsal target genes from the crustacean, Parhyale hawaiensis.
Parhyale is an ideal outgroup to study the evolution of Dorsal cis-regulatory targets not only because of its phylogenetic position, but because it is highly amenable to wet-lab experimentation. It is easy to rear and most of the embryological and molecular techniques developed over the last 100 years of fruit fly research appear to be directly applicable to Parhyale.
Publications
Senger K, Armstrong GW, Rowell WJ, Kwan JM, Markstein M, Levine M.(2004) Immunity Regulatory DNAs Share Common Organizational Features in Drosophila.
Mol Cell. 13, 19-32.
Stathopoulos A, Van Drenth M, Erives A, Markstein M, Levine M. (2002)
Whole-Genome Analysis of Dorsal-Ventral Patterning in the Drosophila Embryo. Cell 111, 687-701.
Markstein M and Levine M. (2002)
Decoding cis-regulatory DNAs in the Drosophila genome.
Curr Opin Genet Dev. 12, 601-606.
Markstein M, Markstein P, Markstein V, and Levine M. (2002)
Genome-wide analysis of clustered Dorsal binding sites identifies putative target genes in the Drosophila embryo. PNAS 99, 763-768.
Posters and Presentations
2003
Invited Talk, San Jose State University
talk: Using Computation in Gene Regulation Discoveries
Enhancer Super Group, UC Berkeley
talk: The Fly Enhancer Algorithm Unveiled
IEEE Bioinformatics Conference, Stanford University
talk: Computing non-coding regulatory DNAs
44th Annual Drosophila Research Conference
talk: Computing Enhancers on the Fly
2002
IEEE Bioinformatics Conference, Stanford University
talk: Biology for Computer Scientists
43rd Annual Drosophila Research Conference
poster: FlyEnhancer.org can help you graduate
2001
Berkeley Department of Genetics and Development Retreat
talk: Genome-wide survey of Dorsal binding site clusters identifies bona fide enhancers
SOFTWARE DEVELOPMENT
2001-present
Collaboration with graduate student in the Computer ScienceDepartment at UC Berkeley to build web interfaces for bioinformatics tools. See www.opengenomics.org
1998-present
Collaborations with computer scientists at Hewlett-Packard Labs to
develop several bioinformatics tools. I have initiated and am currently involved in developing pattern matching programs to rapidly identify cis-regulatory DNAs. This effort resulted in the development of Fly Enhancer, a search engine which rapidly scans the entire fly genome for clusters of short sequences of nucleotides. We are currently developing and optimizing a second program, MERmaid, which rapidly identifies novel motifs shared between coordinately regulated enhancers.
EDUCATION
2003 Ph.D., Committee on Developmental Biology
University of Chicago
Visiting Scholar, University of California at Berkeley, 2000-2003
1991 B.S., Zoology
University of Texas at Austin
ACADEMIC SERVICE
2001-present ad hoc peer-reviewer for Developmental Biology and PNAS
RELATED WORK EXPERIENCE
1994-1996
Research Associate
UCSF, laboratories of Dr. Holly Ingraham and Dr. Raul Andino
In the Ingraham lab I established a Xenopus oocyte assay system to study the proteolytic processing of TGF-b related molecules involved in mammalian sex differentiation. In the Andino lab, I engineered epitope tags into polio virus proteins to track their localization in infected host cells.
1991
Cytogenetics Technician
Genentrix, Alameda , CA
Analyzed human karyotypes for abnormalities.
1988-1990
Undergraduate Research Assistant
University of Texas at Austin, laboratory of Dr. Gary Freeman
Assisted a graduate student in classical cut and paste experiments on the early embryo of the snail, Illyanasa. Also wrote computer program to interpret electron diffraction data.
