Dr. Roeder’s broad objectives are to understand the specific regulatory events that control these processes, as well as more fundamental aspects of transcription activation and repression mechanisms. To this end, his specific objectives are to determine the nature and mechanism of action of both the general transcription machinery that is commonly used by all genes and the gene- and cell-type-specific factors that directly regulate target genes in response to various growth, developmental and stress stimuli.

His lab’s multipronged experimental strategy begins with the use of a biochemical tool called the cell-free system, pioneered by Dr. Roeder, that allows researchers to recreate the essence of transcription in a test tube with cloned genes and cellular extracts. They then biochemically dissect these systems, purify and clone the individual factors and study the structure, function and regulation of these factors by a combination of biochemical and genetic (i.e., transgenic, knockout and knockin mice) analyses.

The actual transcription of protein-coding genes is mediated directly by RNA polymerase II and a number of common initiation factors (TFIID, TFIIA, TFIIB, 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 (notably the TATA box and initiator elements) by the multisubunit TFIID.

These factors — comprising the general transcription machinery — represent the ultimate targets of the various gene-specific factors. However, despite the specificity intrinsic to the gene-specific transcriptional regulatory proteins, the complexity of the general transcription machinery (about 44 distinct polypeptides), and documented physical interactions among these components, other “cofactors” have been found essential for functional communication between the gene-specific activators/repressors and the general transcription machinery on specific target genes.

Dr. Roeder’s work is now heavily focused on these cofactors (both coactivators and corepressors), many of which are structurally complex. They include cofactors (e.g., multisubunit histone acetyltransferase, methyltransferase and ubiquitination complexes) that alter the structure of the natural chromatin template, cofactors (e.g., the 30-subunit Mediator complex and negative regulators NC-2 and Gdown-1) that act directly on the general transcription machinery, and a variety of gene- and/or activator-specific factors (e.g., the B cell-specific OCA-B and the inducible PGC-1 implicated in energy metabolism). Current activities focus on transcriptional activators (and corresponding genetic regulatory pathways) important for: homeostasis (nuclear receptors such as thyroid hormone receptor, estrogen receptor, estrogen-related receptor and peroxisome proliferation-activated receptor); lymphoid/myeloid cell differentiation and malignancy (OCT-1/2, NFKB and OCA-B; E2A and leukemogenic fusion proteins E2A-HLA and E2A-Pbx1; AML and the leukemogenic AML-ETO fusion protein; mixed lineage leukemia factor [MLL-1] and its leukemogenic fusion partners); and DNA damage responses (tumor suppressor p53 and related family members).

Apart from detailing the mechanisms by which specific target genes are activated by individual transcriptional activators and essential cofactors, the Roeder laboratory also is interested in determining differential usage of cofactors by different activators or by the same activator in different cell types or on different target genes and, especially, how variations in cofactors can dictate cell fate (e.g., growth arrest versus apoptosis in p53-dependent DNA damage responses).

CAREER

Dr. Roeder received his Ph.D. in biochemistry in 1969 from the University of Washington, Seattle, where he worked with William Rutter. He did postdoctoral work with Donald D. Brown at the Carnegie Institution of Washington, in Baltimore, from 1969 to 1971. He was a member of the faculty at Washington University School of Medicine in St. Louis from 1971 to 1982, when he joined The Rockefeller University. In 1985, he was named Arnold and Mabel Beckman Professor.

Dr. Roeder received the 2003 Albert Lasker Award for Basic Medical Research. He shared the 2002 ASBMB-Merck Award, the 2000 Gairdner Foundation International Award, the 1999 Louisa Gross Horwitz Prize and the 1999 General Motors Cancer Research Foundation’s Alfred P. Sloan Prize. He is a member of the National Academy of Sciences.