jbj101

James B. Jaynes, PhD

Contact Dr. Jaynes

1020 Locust Street
Room JAH-490
Philadelphia, PA 19107

(215) 503-4778

Medical School

Seattle, University of Washington, BS, Physics

Expertise and 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.

Other Expertise

In a collaborative project with the Alex Mazo laboratory, we are studying the functions of the novel histone methyltransferase Trithorax-related (TRR). These studies reveal that this protein is a coactivator of the nuclear receptor complex of EcR-USP, acting in conjunction with ecdysone to up-regulate hedgehog gene expression during morphogenetic furrow progression in Drosophila eye development. This is the first H3-K4 methylase known to be directly involved in steroid hormone-regulated gene expression.

Industrial Relevance

Please see sections on expertise.

Keywords

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