Heads of Laboratories
Arnold and Mabel Beckman Professor
Laboratory of Biochemistry and Molecular Biology
Gene expression is controlled primarily at the level of transcription, the process by which genes are copied into RNA for translation into proteins. A central question in biology is how the gene- and cell type-specific transcription of the approximately 25,000 genes of the human genome is regulated. Dr. Roeder studies the transcription factors, including epigenetic factors, and underlying mechanisms that are involved in this regulation.
Differential gene expression, regulated primarily at the level of transcription, underlies key events in development, cell growth and differentiation, homeostasis, and pathologies such as cancer. The transcription programs central to these events are governed by cell-specific master transcription factors bound to specific enhancer and promoter elements, with the extraordinary power and significance of such factors being profoundly demonstrated by the ability of very small subsets to reprogram somatic cells to a pluripotent state. Dr. Roeder’s major objectives are to determine the mechanisms by which such factors, acting ultimately upon the general transcription machinery, activate or repress specific target genes in various physiological processes.
The Roeder lab’s multipronged experimental strategy emphasizes powerful cell-free systems, pioneered by Dr. Roeder, that recreate the essence of transcription in a test tube with cloned genes and factors purified (and subsequently cloned) from cellular extracts. The structure, function, mechanism of action, and regulation of these factors is then studied by a combination of biochemical, cell-based, and genetic (i.e., transgenic, knockout, and knockin mice) analyses.
The actual transcription of protein-coding genes is mediated by RNA polymerase II and cognate initiation factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH) that form functional preinitiation complexes on promoters via an ordered assembly pathway that begins with recognition of common core promoter elements (e.g., TATA box) by the multisubunit TFIID. These factors — comprising the general transcription machinery — represent the ultimate targets of the various gene-specific factors. However, other “cofactors” are essential for functional communication between the gene-specific factors, to which they bind, and the general transcription machinery.
Dr. Roeder’s work is now heavily focused on these cofactors, many of which are structurally complex. They include cofactors (e.g., multi-subunit histone acetyl- and methyl-transferase complexes) that alter the structure of the natural chromatin template, cofactors (e.g., the 30-subunit Mediator) that act directly on the general transcription machinery, and a variety of cell/activator-specific cofactors (e.g., the B cell-specific OCA-B and the inducible PGC-1 implicated in energy metabolism).
Current activities focus on transcriptional activators important for homeostasis (nuclear hormone receptors); lymphoid cell differentiation (E2A, OCT1/2, OCA-B) and malignancy (E2A-PBX1, AML1-ETO, and MLL1-AF9 leukemogenic fusion proteins); and tumor suppression (p53).
Apart from detailing the mechanisms by which specific target genes are activated by individual transcriptional activators and associated cofactors, the Roeder laboratory also is interested in determining the basis for differential usage of cofactors by individual activators in varied contexts, how variations in cofactor usage can dictate cell fate (e.g., growth arrest versus apoptosis in p53-dependent DNA damage responses), and, in the case of leukemic fusion proteins, potential therapeutic targets.
B.A. in chemistry, 1964
M.S. in chemistry, 1965
University of Illinois
Ph.D. in biochemistry, 1969
University of Washington
Carnegie Institution of Washington, 1969–1971
Assistant Professor, 1971–1975
Associate Professor, 1975–1976
Washington University School of Medicine
The Rockefeller University
National Academy of Sciences U.S. Steel Award, 1986
Louisa Gross Horwitz Prize, 1999
Alfred P. Sloan Prize, General Motors Cancer Research Foundation, 1999
Canada Gairdner International Award, 2000
ASBMB-Merck Award, 2002
Albert Lasker Basic Medical Research Award, 2003
Salk Institute Medal for Research Excellence, 2010
Albany Medical Center Prize, 2012
National Academy of Sciences
American Academy of Arts and Sciences
Fellow, American Association for the Advancement of Science
Iida, S. et al. PRDM16 enhances nuclear receptor-dependent transcription of the brown fat-specific Ucp1 gene through interactions with Mediator subunit MED1. Genes Dev. 29, 308–321 (2015).
Cevher, M.A. et al. Reconstitution of active human core Mediator complex reveals a critical role of the MED14 subunit. Nat. Struct. Mol. Biol. 21, 1028–1034 (2014).
Tang, Z. et al. SET1 and p300 act synergistically, through coupled histone modifications, in transcriptional activation by p53. Cell 154, 297–310 (2013).
Sun, X.J. et al. A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis. Nature 500, 93-97 (2013).
Chen, W. et al. A muscle-specific knockout implicates nuclear receptor coactivator MED1 in the regulation of glucose and energy metabolism. Proc. Natl. Acad. Sci. U.S.A. 107, 10196–10201 (2010).