Vanderbilt-Ingram Cancer Center

The VICC.ORG Directory of Doctors, Healthcare Providers & Researchers

Eugene M Oltz, Ph.D.

Professor of Microbiology and Immunology
VICC Member
Researcher

Contact Information:

Vanderbilt University Medical Center
A-4203 Medical Center North
Nashville, TN 37232-2363
615-343-3011

Research Specialty

Genetic and epigenetic programming of lymphocyte development

Research Description

As we forge into the post-genomic era of biomedical research, it has become clear that many diseases do not originate from lesions or inherited differences in our genomes. Indeed, genetically identical twins often exhibit distinct appearances or disease susceptibilities. Instead of having a true genetic basis, many diseases are rooted in chemical tags placed on DNA or on histones, the proteins that package the genome and control its function. These so-called epigenetic modifications can significantly alter gene expression patterns either transiently or long-term. Directed changes in gene expression required for mammalian development, organogenesis, stem cell differentiation, and aging are largely specified by the complex language of epigenomics. Alterations in normal epigenetic patterns have now been linked etiologically to numerous diseases including cancer, autoimmunity, and a growing number of neurological disorders. For example, tumor suppressor genes are silenced in many cancer cells via DNA hypermethylation.

More and more evidence indicates that environmental factors also have a profound impact on the epigenome and at least some chemical- or diet-induced changes may be heritable. As stated by a recent PBS program on epigenetics, our health is affected not only by the environment to which we are exposed but also by what our parents and grandparents ate, drank, or breathed (pbs.org/wgbh/nova/sciencenow/3411/02.html). In contrast to the immutability of genetic lesions, epigenetic modifications are reversible in nature. In this regard, compounds that modify DNA methylation or histone acetylation are clinically employed for treating certain cancers and neurological disorders. As one example, the FDA recently approved a histone deacetylase inhibitor, termed vorinostat, for treatment of cutaneous T-cell lymphoma. Thus, a better understanding of epigenomics is expected to generate entirely new avenues for diagnostics and therapeutic intervention.

Our laboratory studies the epigenetic regulation of lymphocyte development, with particular focus on a process that assembles the enormous diversity of antigen receptor genes required for mammalian immunity, termed V(D)J recombination. All of these immunoglobulin (Ig) and T cell receptor (TCR) genes span megabases in the genome and their assembly is regulated by local, regional and long-range epigenetic mechanisms. These three levels of control are essential for guiding lymphocytes through their developmental programs and targeting genetic recombination to precise regions within a selected Ig or TCR locus. Indeed, when these epigenetic mechanisms go awry and recombinase is aberrantly targeted, it may produce a chromosomal translocation -- a type of genetic lesion that underlies most leukemias and lymphomas. As such, antigen receptor loci provide attractive models to study dynamic epigenetic regulation of gene expression with clinically relevant implications.

Our approach to deciphering the epigenetic control of Ig and TCR loci has three major prongs. First, we are dissecting the basic mechanisms of cross-talk between genetic control elements (promoters, enhancers, etc.) and epigenetic modifications that facilitate or repress V(D)J recombination. Second, we are screening large chemical libraries (>120,000 compounds) to discover small molecule inhibitors of histone modifying enzymes tied to oncogenic changes in the epigenome of tumor cells. Third, we have initiated studies to define the entire epigenome of lymphocytes and how this landscape changes during normal development or pathologic transformation into leukemias and lymphomas. Together, our studies are expected to yield new insights into epigenetic control mechanisms that guide developmental-specific changes in gene expression. In turn, our findings will yield new biomarkers and therapies for the diagnosis and treatment of immunologic diseases, including lymphoid tumors.