Chromatin & Gene Expression Group
Chromatin, Epigenetics & Transcription
Trevor K. Archer, Ph.D.
Principal Investigator and Chief, Molecular Carcinogenesis Laboratory
The American Cancer Society predicts that there will be ~1.4 million new cancer cases and ~560,000 deaths in 2007. Thus, despite the recent declines in death and incidences from most cancers, the disease remains a potent and vital public health concern for the nation and central to the mission of the NIEHS (See the National Cancer Institute Cancer Trends Progress Report ). Both the magnitude of the problem and the diversity of diseases that appear to comprise "cancer" have lead to an intense increase in fundamental cancer research. While this research has developed along multiple avenues, efforts in the areas of chromatin & epigenetics, the ubiquitin-proteasome system (UPS), and stem cell biology have become particularly intense.
In human cells, DNA is organized with the aid of small basic proteins, histones, to form chromatin. The nucleosome, comprising 147 base pairs of DNA and 2 copies each of histones H2a, H2b, H3 and H4, is the fundamental organizing principle of chromatin. It is this architecture that is the substrate for epigenetic regulation. Biological processes have to overcome this inherently repressive structure and do so with the aid of two classes of enzymes. The first class disrupts chromatin structure using ATP-dependent chromatin remodeling, and the second class mediates the covalent modification of histone proteins. These enzymes and their activities often are altered in cancer cells, thus becoming important targets for novel therapeutics.
The mechanisms by which cells regulate the steady state levels of proteins is clearly critical to understanding disease. While cells have multiple systems for protein degradation, the ubiquitin-proteasome system (UPS) as possibly the best described and most actively studied. The UPS is both highly complex and tightly regulated perhaps contributing to its relevance to human health and disease, particularly cancer. Indeed drugs targeting the UPS represent potentially important treatments for specific cancers and neurodegenerative diseases.
The development of human embryonic stem cells almost 10 years ago ushered in a exciting and controversial era in molecular medicine. The shared characteristic for continuous self renewal and ability to differentiate into all cell types is thought to imbue these cells with great therapeutic potential. For this reason, the mechanisms that underpin reprogramming of the genetic repertoire of these cells represent attractive targets for chromatin and epigenetic studies.
Major areas of research:
- Evaluating how chromatin remodeling complexes and transcription factors function in transcription from chromatin
- Analyzing the ubiquitin proteasome system interface with chromatin remodeling, epigenetics and hormone signaling
- Exploring how chromatin and epigenetics contribute to human ES cell pluripotency
- What is the biological significance of the BRG1 chromatin remodeling complex?
- What is the role of NF1 in chromatin remodeling of at glucocorticoid responsive promoters?
- What distinguishes genetic responses to hormones and the Proteasome?
- What is the epigenetic impact of proteasome inhibition?
- Do environmental exposures alter hESC chromatin remodeling proteins?
- How do epigenetic factors regulate pluripotency in human ES cells?
Trevor A. Archer, Ph.D., leads the Chromatin & Gene Expression Group and is Chief of the Laboratory of Molecular Carcinogenesis. He earned his Ph.D. in 1987 at Queen’s University, Kingston Ontario Canada. He has published more than 60 peer-reviewed articles in leading biomedical journals as well as several book chapters. He served as a Tenured Associate Professor in the Departments of Biochemistry and Obstetrics and Gynecology at the University of Western Ontario in London Canada before joining NIEHS in 1999.