Miki Fujioka, PhD
Philadelphia, PA 19107
Most Recent Peer-reviewed Publications
- Engrailed cooperates directly with Extradenticle and Homothorax on a distinct class of homeodomain binding sites to repress sloppy paired
- Regulation of a duplicated locus: Drosophila sloppy paired is replete with functionally overlapping enhancers
- Ecdysone- and NO-Mediated Gene Regulation by Competing EcR/Usp and E75A Nuclear Receptors during Drosophila Development
- Non-additive interactions involving two distinct elements mediate sloppy-paired regulation by pair-rule transcription factors
- A chromatin insulator mediates transgene homing and very long-range enhancer-promoter communication
Expertise & Research Interests
Embryos regulate their growth and development in many ways, but control of gene transcription is particularly important for directing cells along particular developmental pathways. In Drosophila, a cascade of nuclear regulatory events establishes very early differences in cell fates by producing intricate patterns of gene expression. Many of these pattern-forming genes encode DNA binding proteins that regulate each others expression, and subsequently instruct the rest of the genome in a manner appropriate to each position in the organism. These regulatory proteins are conserved across the evolutionary distance separating flies and humans. This applies to both their primary structure, implying similarity in mechanism, and often their developmental function. That is, the regulatory scheme in which they function solves a common problem of developing multi-cellular organisms. Our current studies revolve around understanding specific mechanisms of two types: first, which gene products interact directly with which genes and other gene products, and second, how this impinges on transcriptional regulation and, relatedly, the stability of the epigenome.
My laboratory focuses on the regulation and function of two homeodomain-containing proteins. The homeodomain is a highly conserved sequence-specific DNA binding domain found in transcriptional regulators from yeast to humans. One of these, Engrailed (En), is a potent repressor of transcription that recruits the corepressor Groucho, a homolog of the TLE family of mammalian cofactors. We are currently studying interactions between En and the Pbx and Meis/PREP families of Hox protein cofactors, which serve to increase its DNA-binding specificity and thereby direct it to particular target genes. The interaction with En confers a novel activity on the Meis/PREP-Pbx complex (in Drosophila, Hth-Exd), that of transcriptional repression. Our analysis focuses on the biochemical interactions among these factors, and on the functional consequences of altering those interactions.
Even-skipped (Eve) is another transcription factor that regulates developmental processes in a highly conserved fashion. Eve, like En, uses both Groucho-dependent and independent mechanisms to repress transcription. With the even-skipped gene (eve), we have the ability to completely rescue null mutants with a transgene, allowing us to functionally replace the endogenous gene. This facilitates our studies of its regulation in vivo. Currently, we are analyzing how long-range repression and activation occur over an entire genetic locus, through the regulation of chromatin structure. Included in the long-range regulatory elements of eve are a boundary region that helps to functionally isolate it from neighboring genes, and to maintain both the activated and repressed state within different developing lineages of cells. These activities are mediated by an insulator and a Polycomb-group response element. Both of these kinds of elements function in a variety of genes, and in mammals as well as in Drosophila, to regulate developmental processes like stem cell maintenance and differentiation. Understanding the underlying mechanisms will provide novel ways to attack problems like cancer, which is caused in part by misregulation of gene expression and chromatin structure.
Biochemistry; Cell Biology; Developmental Biology; Genetics; Human Physiology; Drosophila; drosophilidae; embryogenesis; gene regulation; transgenic animal; transcription factor; developmental genetics; invertebrate embryology; genetic promoter element; transcriptional regulation; chromatin; epigenetics; gene induction; gene repression; insulator; Polycomb group; maintenance element; protein structure-function