Our Science – Lewis Website

Brian A. Lewis, Ph.D.

Metabolism Branch Investigator Bldg. 10, Rm. 4N112 9000 Rockville Pike Bethesda, MD 20892 Phone:   301-435-8323 Fax:   Fax Number not listed E-Mail:   LEWISBRI@MAIL.NIH.GOV

Biography

Visiting Scientist, NCI, NIH 2006-2008 (affiliated with NYU School of Medicine)

Research Assistant Professor/Senior Fellow 2000-2006
UMDNJ, Department of Biochemistry

Postdoctoral Fellow 1993-2000 Children's Hospital,
Harvard Medical School

Ph.D. 1993 Molecular Biology, Princeton University

B.A. 1988 University of Virginia

Research

My lab is a new addition to the Metabolism Branch/CCR/NCI and will focus on understanding transcriptional initiation largely through protein biochemistry using functional cell-free systems. In addition, the lab will be exploiting ChIP, ChIP-chip, and siRNA techniques, which are powerful additions to the biochemist’s arsenal in establishing the in vivo relevance of the cell-free systems. There are three projects in the lab that address specific problems in eukaryotic transcriptional regulation.

The first project will be concerned with identifying the proteins necessary for the B-cell specific transcriptional activity of several B-cell transcriptional activators. These are important issues as many B-cell cancers are causally related to the dysregulation of B-cell specific transcription events. A greater understanding of B-cell specific transcription is a necessary prerequisite to a better understanding of how perturbations in regulation promote tumorigenesis and how these particular activators have effects in only subsets of B-cell tumors. Additionally, our understanding of tissue-specific transcriptional biochemistry is very limited. Thus, I expect to use the work on B-cell specific transcription as a possible paradigm to modeling tissue-specific transcription in general.

The second project is a new interest of mine and whose goal is to understand the functional requirement of the O-GlcNAc post-translational modification (PTM) of RNA polymerase II. The O-GlcNAc PTM is also of general interest both as an understudied PTM, and as a glucose sensor linked to type II diabetes. My experiments thus far show a significant transcriptional defect upon the disruption of GlcNAc cycling and that RNA polymerase II is a functional target of O-GlcNAc action. This work shows that the O-GlcNAc modification creates a novel functional form of RNA polymerase II, and is the first evidence of a PTM of the pol II CTD is necessary for transcription initiation. Future work will involve addressing the role of this cycling in transcriptional initiation and what proteins are involved in establishing and regulating the cycle.

The third project is a long-standing interest of mine to understand the regulation of core promoter-specific transcription in the human genome. This work is especially important as only about 10% of promoters in the human genome contain the well-known TATA box on which most of our current knowledge of core promoters is based. My previous work led to the identification of the downstream core element (DCE), one of five known core promoter elements. Additional work showed that the general transcriptional machinery is insufficient for the function of all core promoter elements and instead, additional proteins are necessary to establish specific transcription from the DPE-class of core promoter elements. Future work will focus on the identification of additional core promoter elements, understanding the functional consequences of different core promoter architectures, and the factor requirements of core promoters.

This page was last updated on 11/7/2008.