Assistant Professor, Skirball Institute of Biomolecular Medicine, Department of Biochemistry and Molecular Pharmacology
Ph.D., 2005 University of Munich
Chromatin, Nucleosome, Epigenetics, Transcription, Cancer, Structure
Skirball Institute of Biomolecular Medicine
540 First Avenue 3rd floor, Lab 17
New York, N.Y. 10016
Fax: (212) 263-8951
Tel: (212) 263-8573
Molecular Studies of Chromatin Structure and Epigenetics
In the eukaryotic nucleus genomic DNA is hierarchically packaged by histone proteins into chromatin. The fundamental repeating unit of chromatin is the nucleosome, which is comprised of ~146 base pairs of DNA wrapped around an octamer of histones. Gene silencing factors such as Polycomb Repressive Complexes (PRC), the Silent Information Regulator (SIR) complex or Heterochromatin Protein 1 (HP1) specifically bind and organize nucleosomes to form higher-order, compacted chromatin structure. Epigenetic modifications of histones are known to regulate binding of these factors. Compaction of chromatin has been proposed to cause gene repression by creating a block to transcription processes. This compaction is crucial for establishment, maintenance and propagation of distinct patterns of gene expression. In higher eukaryotes, defective gene silencing can result in developmental defects, cellular transformation and malignant outgrowth.
Understanding how chromatin structure and genome architecture regulate gene expression is one of the most important, unexplained frontiers in biology. The goal of our laboratory is to understand the organization and dynamics of chromatin complexes important for the regulation of gene expression both at the genetic and epigenetic levels. We use a combination of structural approaches, including x-ray crystallography and electron microscopy, coupled with biophysical and biochemical experimentation to study mechanisms by which gene silencing complexes impact chromatin structure and repress transcription.
Molecular details of these complexes will be pivotal to understanding their biological function in both normal and disease states and will be central to the development of novel epigenetics-based therapeutics.
- Armache, K. J., Garlick, J. D., Canzio, D., Narlikar, G. J., and Kingston, R. E. (2011) Structural Basis of Silencing: Sir3 BAH Domain in Complex with a Nucleosome at 3.0 Å Resolution, Science 334, 977-82.PMID:22096199
- Kostrewa, D*., Zeller, M*. E., Armache, K. J*., Seizl, M., Leike, K., Thomm, M., and Cramer, P. (2009) RNA Polymerase II-TFIIB Structure and Mechanism of Transcription Initiation, Nature 462, 323-330. * Equal contribution. PMID: 19820686
- Armache, K. J., Mitterweger, S., Meinhart, A., and Cramer, P. (2005) Structures of Complete RNA Polymerase II and Its Subcomplex, Rpb4/7, J Biol Chem 280, 7131-7134. PMID:15591044
- Kettenberger, H*., Armache, K. J*., and Cramer, P. (2004) Complete RNA Polymerase II Elongation Complex Structure and Its Interactions with NTP and TFIIS, Mol Cell 16, 955-965. * Equal contribution. PMID:15610738
- Armache, K. J., Kettenberger, H., and Cramer, P. (2003) Architecture of Initiation-Competent 12-Subunit RNA Polymerase II, Proc Natl Acad Sci U S A 100, 6964-6968. PMID:12746495