Eugene M. Oltz, Ph.D.

Professor
Pathology and Immunology

Immunology Program
Molecular Genetics and Genomics Program
Biochemistry, Biophysics, and Structural Biology Program

  • 314-362-5515

  • 314-362-5524

  • 314-362-8888

  • 8118

  • 7730 CSRB

  • eoltz@WUSTL.EDU

  • http://www.pathology.wustl.edu/labs/oltz/

  • cancer, chromatin, epigenetics, genome rearrangements, lymphocytes, transcriptional regulation

  • Genetic and epigenetic programs that guide normal lymphocyte development and contribute to cellular transformation

Research Abstract:

Epigenetic Control of Lymphocyte Gene Expression in Health and Disease

As we move into the post-genomic era, we are grappling with the realization that many diseases do not originate from lesions or inherited differences in our genomes. For example, genetically identical twins often exhibit distinct appearances or disease susceptibilities as they age. Instead of having a purely genetic basis, numerous diseases are rooted in the chemical tags placed on DNA or on the proteins that package our genome. Patterns of these epigenetic modifications, collectively called the epigenome, control the initial phases of gene activation or repression to guide nearly all biological processes, including stem cell differentiation, mammalian development, and aging. The Oltz lab studies changes in the epigenome that guide processes critical for lymphocyte development and the diversification of antigen receptor genes. In addition, we have made considerable progress toward identifying recurrent aberrations in the epigenome of lymphoid tumors, with the ultimate goal of reversing their abnormal signatures via targeted therapies.

The focus of this latter project is non-Hodgkin lymphoma (NHL), a common form of cancer that is prevalent in older adults. Treatment of NHL would benefit greatly from the advent of early diagnostics and new therapeutics. The emerging field of epigenomics is expected to provide such opportunities for most diseases, including NHL. In contrast to the immutability of disease-causing genetic lesions, epigenetic modifications are reversible, offering the possibility of new therapeutic modalities. We suspect that the epigenome of NHL tumors from different patients will harbor common signatures that can be used as reporters for the disease and provide insights into mechanisms of gene regulation that drive the disease. To identify these tumor-specific signatures in the epigenome, we have initiated multi-disciplinary collaborations between basic and clinical scientists that will (i) compare the epigenomes of primary NHL tumors with matched circulating B cells from each patient, (ii) identify genetic elements governing the inappropriate expression of NHL gene cohorts, and (iii) innovate a therapeutic approach called Focused Epigenetic Therapy of Control Hubs (FETCH), in which control elements are targeted for reversal of their abnormal epigenetic landscape. Together, these studies will not only provide a foundational dataset for gauging the feasibility of epigenomic approaches to NHL, but will also guide future efforts to develop precision epigenetic therapies for reversing aberrant expression patterns that characterize a wide range of human diseases.

A second interest of our laboratory is the epigenetic regulation of normal lymphocyte development, with a 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 the 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 locus. 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 types of leukemia and lymphoma. As such, antigen receptor loci provide attractive models to study dynamic epigenetic regulation of gene expression with clinically relevant implications. Using a combination of in vitro and in vivo approaches, 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. Together, our studies should provide valuable insights into the chromosomal dynamics that guide antigen receptor gene assembly, while preventing aberrant interactions that lead to oncogenic translocations with other chromosomes.

Selected Publications:

Zhao JY, Osipovich O, Koues OI, Majumder K, Oltz EM. "Activation of Mouse Tcrb: Uncoupling RUNX1 Function from Its Cooperative Binding with ETS1." Journal of Immunology Volume 199, Aug 2017, p1131-1141.

Huang Y, Koues OI, Zhao JY, Liu R, Pyfrom SC, Payton JE, Oltz EM. "cis-Regulatory Circuits Regulating NEK6 Kinase Overexpression in Transformed B Cells Are Super-Enhancer Independent." Cell Volume 18, Issue 12, p2918-2931, 21 March 2017.

Kaiko GE, Ryu SH, Koues OI, Collins PL, Solnica-Krezel L, Pearce EJ, Pearce EL, Oltz EM, Stappenbeck TS. "The Colonic Crypt Protects Stem Cells from Microbiota-Derived Metabolites" . Cell 165(7):1708-20 (2016).

Koues OI, Collins PL, Cella M, Robinette ML, Porter SI, Pyfrom SC, Payton JE, Colonna M, Oltz EM. "Distinct Gene Regulatory Pathways for Human Innate versus Adaptive Lymphoid Cells." Cell. 2016 May 19;165(5):1134-46. PMID:27156452

Kaiko GE, Ryu SH, Koues OI, Collins PL, Solnica-Krezel L, Pearce EJ, Pearce EL, Oltz EM, Stappenbeck TS. "The Colonic Crypt Protects Stem Cells from Microbiota-Derived Metabolites." Cell. 2016 Jun 16;165(7):1708-20. PMID:27264604

Majumder K, Rupp LJ, Yang-Iott KS, Koues OI, Kyle KE, Bassing CH, Oltz EM. Domain-Specific and Stage-Intrinsic Changes in Tcrb Conformation during Thymocyte Development. J Immunol. 2015 Aug 1;195(3):1262-72. PMCID: PMC4506872

Collins PL, Kyle KE, Egawa T, Shinkai Y, Oltz EM. The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes. Proc. Natl. Acad. Sci., USA, 2015 Jul 7;112(27):8367-72. PMCID: PMC4500218

Koues OI, Kowalewski RA, Chang LW, Pyfrom SC, Schmidt JA, Luo H, Sandoval LE, Hughes TB, Bednarski JJ, Cashen AF, Payton JE, Oltz EM. Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma. Immunity. 2015 Jan 20;42(1):186-98. PMCID: PMC4302272

Majumder K, Koues OI, Chan EA, Kyle KE, Horowitz JE, Yang-Iott K, Bassing CH, Taniuchi I, Krangel MS, Oltz EM. Lineage-specific compaction of Tcrb requires a chromatin barrier to protect the function of a long-range tethering element. J Exp Med. 2015 Jan 12;212(1):107-20. PMCID: PMC4291525.

Predeus AV, Gopalakrishnan S, Huang Y, Tang J, Feeney AJ, Oltz EM, Artyomov MN. Targeted chromatin profiling reveals novel enhancers in Ig H and Ig L chain Loci. J Immunol. 2014 Feb 1;192(3):1064-70. PMCID: PMC4096788

Gopalakrishnan S, Majumder K, Predeus A, Huang Y, Koues O, Verma-Gaur J, Loguerico S, Su AI, Feeney AJ, Artyomov M, Oltz EM. A Unifying Model for Molecular Determinants of the Pre-selection Vβ Repertoire. Proc. Natl. Acad. Sci., USA, 2013 Aug 20;110(34):E3206-15. PMCID: PMC3752219

Guo C, Gerasimova T, Hao H, Ivanova I, Chakraborty T, Selimyan R, Oltz EM, Sen R. Two forms of loops generate the chromatin conformation of the immunoglobulin heavy-chain gene locus. Cell. 2011 Oct 14;147(2):332-43. PMCID: PMC3685183

Ise W, Kohyama M, Schraml BU, Zhang T, Schwer B, Basu U, Alt FW, Tang J, Oltz EM, Murphy TL, Murphy KM. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat Immunol. 2011 Jun;12(6):536-43. PMCID: PMC3117275

Ji Y, Little AJ, Banerjee JK, Hao B, Oltz EM, Krangel MS, Schatz DG. Promoters, enhancers, and transcription target RAG1 binding during V(D)J recombination. J Exp Med. 2010 Dec 20;207(13):2809-16. PMCID: PMC3005232

Last Updated: 8/29/2016 4:29:07 PM

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