Philadelphia University + Thomas Jefferson University

Jaynes, James B.

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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
PhD, University of Washington, Seattle, WA, Biochemistry

Expertise & Research Interests

Current work in the laboratory of James B. Jaynes is focused on understanding two major aspects of nuclear genome regulation in eukaryotic organisms that affect genome organization in 3 dimensions. We and others have shown that these regulatory systems have a major impact on the packaging and utilization of the genome. The first is repression (and sometimes activation) of gene expression through structural changes in chromatin by the Polycomb group of chromatin regulators, which work in part through modification of histone side chains. The second is the organization of chromosomal loops by chromatin insulators, which impacts several aspects of chromosome function. These include gene expression (by either facilitating or blocking interactions between enhancers and promoters), DNA recombination and repair (by influencing which linearly distant DNA sequences are accessible to each other and which are not), chromatin compaction during mitosis and meiosis, and epigenetic maintenance of gene expression. Insulators may facilitate epigenetic maintenance by helping to keep sister chromatids aligned following DNA replication, thereby allowing histone modifications, such as those propagated by the Polycomb group, to be faithfully templated from one cellular generation to the next. 

We are analyzing how long-range repression and activation occur over an entire genetic locus, even skipped (eve), and its genomic neighborhood, through the regulation of chromatin structure. The eve gene is flanked by insulators (called homie and nhomie) that functionally isolate it from neighboring genes. Along with Polycomb-group response elements, they maintain both the activated and repressed state within different developing lineages of cells. Both of these kinds of elements function in a variety of genes, and in mammals as well as in Drosophila, to regulate developmental processes such as stem cell maintenance and differentiation. Understanding the mechanisms will provide novel ways to attack cancer, which is caused in large part by mis-regulation of gene expression and chromatin structure.

Other Expertise

Another focus of the laboratory has been to understand the biochemical basis of combinatorial control of gene transcription by DNA binding proteins. Embryos regulate their growth and development in many ways, but control of gene transcription is essential 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 studies 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 study 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 homeodomain transcription factor that regulates developmental processes in a highly conserved fashion. Eve, like En, uses both Groucho-dependent and -independent mechanisms to repress transcription. The combinatorial regulation of gene expression by the homeodomain superfamily of transcription factors serves as a paradigm for understanding how cell-type specificity and intercellular signaling are integrated by DNA elements in all eukaryotic organisms. 

Industrial Relevance

Please see sections on expertise.

Keywords

Biochemistry; Cell Biology; Developmental Biology; Genetics; Drosophila; insulator; boundary element; Polycomb group maintenance element; embryogenesis; gene regulation; transgenic animal; transcription factor; developmental genetics; invertebrate embryology; genetic promoter element; transcriptional regulation; chromatin; epigenetics; gene induction; gene repression

Publications

Most Recent Peer-Reviewed Publications

  1. Using competition assays to quantitatively model cooperative binding by transcription factors and other ligands
  2. Boundaries of loop domains (insulators): Determinants of chromosome form and function in multicellular eukaryotes
  3. Determinants of Chromosome Architecture: Insulator Pairing in cis and in trans
  4. Genome-wide identification of Drosophila Hb9 targets reveals a pivotal role in directing the transcriptome within eight neuronal lineages, including activation of Nitric oxide synthase and Fd59a/Fox-D
  5. The Drosophila eve Insulator Homie Promotes eve Expression and Protects the Adjacent Gene from Repression by Polycomb Spreading
  6. Engrailed cooperates directly with Extradenticle and Homothorax on a distinct class of homeodomain binding sites to repress sloppy paired
  7. Regulation of a duplicated locus: Drosophila sloppy paired is replete with functionally overlapping enhancers
  8. Ecdysone- and NO-Mediated Gene Regulation by Competing EcR/Usp and E75A Nuclear Receptors during Drosophila Development
  9. A chromatin insulator mediates transgene homing and very long-range enhancer-promoter communication
  10. The DNA-binding Polycomb-group protein Pleiohomeotic maintains both active and repressed transcriptional states through a single site
  11. The interaction of DIAP1 with dOmi/HtrA2 regulates cell death in Drosophila
  12. Transcription of bxd Noncoding RNAs Promoted by Trithorax Represses Ubx in cis by Transcriptional Interference
  13. Embryonic even skipped-dependent muscle and heart cell fates are required for normal adult activity, heart function, and lifespan
  14. Erratum: Drawing lines in the sand: Even skipped et al. and parasegment boundaries (Developmental Biology (2004) 269 (609-622) DOI: 10.1016/j.ydbio. 2004.03.001)
  15. Drawing lines in the sand: Even skipped et al. and parasegment boundaries
  16. Embryonic origins of a motor system: Motor dendrites form a myotopic map in Drosophila
  17. Methylation at lysine 4 of histone H3 in ecdysone-dependent development of Drosophila
  18. Specification of Motoneuron Fate in Drosophila: Integration of Positive and Negative Transcription Factor Inputs by a Minimal eve Enhancer
  19. Even-skipped, acting as a repressor, regulates axonal projections in Drosophila
  20. Engrailed cooperates with extradenticle and homothorax to repress target genes in Drosophila