Description:

The Department of Biochemistry & Molecular Genetics presents:

Robert G. Roeder, PhD

Arnold and Mabel Beckman Professor
Head of Laboratory of Biochemistry and Molecular Biology
The Rockefeller University, New York, NY

Presentation:

"Mechanistic Studies of Transcriptional Regulation in Hematopoietic Malignancies"

Abstract:

Our laboratory is interested in biochemical mechanisms underlying transcriptional regulation by gene- and cell-specific DNA-binding factors in both normal (development, cell differentiation) and pathological (cancer) physiological processes -- and in particular the functions of transcriptional co-activators that include both chromatin modifying factors and other factors (e.g., Mediator and TAFs) that facilitate more direct communication between enhancer-bound regulatory factors and the general transcriptional machinery at the promoter. In the area of hematopoietic malignancies, we have major interests in the mechanism of action of the B cell-specific transcriptional co-activator OCA-B, which is critical for formation of germinal centers and implicated in GCB cell-derived lymphomas, and leukemic fusion proteins that include RUNX1-ETO, E2A-PBX1 and MLL-AF9/ENL. The presentation will describe recent studies that have identified new direct target genes and new mechanisms both for recruitment of these factors to target genes and for downstream effector functions.

Biosketch:  

Robert G. Roeder is currently the Arnold and Mabel Beckman Professor and Head of the Laboratory of Biochemistry and Molecular Biology at The Rockefeller University. For over 50 years he has pioneered biochemical studies of transcriptional regulatory mechanisms in animal cells.  These include discovery and characterization of RNA polymerases I, II and III, cognate classes of initiation factors, the prototype transcriptional activator in eukaryotes, and a variety of ubiquitous and tissue-specific coactivators. Current studies focus on transcriptional regulation through diverse coactivators that include both chromatin modifying factors and factors (e.g., Mediator and cell-specific coactivators) that act more directly on the general transcriptional machinery. Dr. Roeder’s seminal accomplishments have been recognized by numerous awards that include election to the U.S. National Academy of Sciences, the NAS-US Steel Award in Molecular Biology, the General Motors Cancer Research Foundation Alfred P. Sloan Prize, the Louisa Gross Horwitz Prize, the Gairdner Foundation International Award, the ASBMB Merck and Herbert Tabor Awards, the Albert Lasker Award in Basic Medical Research, the Salk Medal for Scientific Excellence, the Albany Medical Center Prize in Medicine and Biomedical Research and, most recently, the 2021Kyoto Prize in Basic Science.

Personal Statement:

Differential gene expression underlies key events in development, cell growth and differentiation, homeostasis, and pathologies such as cancer -- and is controlled primarily at the level of transcription. The execution and regulation of transcription is effected through a complex array of RNA polymerases, general initiation and elongation factors, gene- and cell-specific DNA-binding regulatory factors, and an increasingly complex array of cofactors that act either on the general transcription machinery or indirectly through chromosomal histone modifications. Over the past 50 years, I have made seminal contributions to both the discovery and an understanding of the structure, function, mechanism of action and regulation of many of these factors. These studies have emphasized the development and application of powerful cell-free transcription systems, reconstituted with purified factors and recombinant DNA or chromatin templates, in order to uniquely, and unequivocally, establish direct functions and mechanisms of action of specific factors on specific genes. At the same time, the biochemical studies have been complemented with cell-based and mouse genetic analyses, along with state of the art genomic and proteomic technologies, both to validate and to guide the in vitro studies. These complementary studies have led to significant new insights into transcriptional regulation in relation to physiological processes that include metabolism and homeostasis, cell growth and differentiation, and cancer -- through studies of nuclear hormone receptors (including PPARg and TRa in adipogenesis), tumor suppressor p53, B cell factors, and leukemic fusion proteins. Recent representative papers:

• C.-S. Chu, J. C. Hellmuth, R. Singh, H.-Y. Ying, L. Skrabanek, M. R. Teater, A. S. Doane, O. Elemento, A. M. Melnick, and R. G. Roeder*. Unique immune cell coactivators specify locus control region function and cell stage. Mol. Cell, 80:845-861.e10, 2020.  PMC7737631 

• K. Ito, M. Schneeberger, A. Gerber, M. Jishage, F. Marchildon, A. V. Maganti, P. Cohen, J.M. Friedman and R.G. Roeder. Critical roles of transcriptional co-activator MED1 in the formation and function of mouse adipose tissues. Genes Dev. 35:729-748, 2021.

• Y.-L. Lee, K. Ito, I.-H. Lin, W.-Y. Chen and R. G. Roeder. Mediator subunit MED1 is required for E2A-PBX1-mediated oncogenic transcription and leukemic cell growth. Proc. Natl. Acad. Sci. USA. 118 (6) e1922864118, 2021. 

• A. Wu, J. Zhi, T. Tian, A. Cihan, M. A. Cevher, Z. Liu, Y. David, T. W. Muir, R. G. Roeder* and M. Yu*. DOT1L Complex Regulates Transcriptional Initiation in Human Cells, Proc. Natl. Acad. Sci. USA. 118:e2106148118, 2021.  PMC8271641  *Co-corresponding authors.

Host: Dr. Shannon Lauberth, Associate Professor, Biochemistry and Molecular Genetics