Karim-Jean Armache, PhD
Assistant Professor, Skirball Institute of Biomolecular Medicine, Department of Biochemistry and Molecular Pharmacology
Biochemistry and Structural biology, chromatin structure, gene expression, stem cells
Epigenetics, RNA Polymerase II, nucleosome
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
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 macromolecular complexes change DNA accessibility to regulate transcription.
All the somatic cells in a multicellular organism are identical with respect to their genomic content. During development cells become different from one another by changing their transcriptional programs. Once these programs are chosen they have to be maintained over many cell divisions through mechanisms of cellular memory. Regulation of DNA accessibility in the nucleus plays a fundamental role in the process of gene transcription.
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 transcriptional processes. This compaction is crucial for establishment, maintenance and propagation of distinct patterns of gene expression. In mammals the activity of gene silencing complexes, chromatin structure and its epigenetic signature is required in embryonic stem cells for the repression of lineage-specific genes in the pluripotent state, and for proper differentiation. 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. 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.
Alpatov R, Lesch BJ, Nakamoto-Kinoshita M, Blanco A, Chen S, Stützer A, Armache KJ, Simon MD, Xu C, Ali M, Murn J, Prisic S, Kutateladze TG, Vakoc CR, Min J, Kingston RE, Fischle W, Warren ST, Page DC, Shi Y. (2014) A Chromatin-Dependent Role of the Fragile X Mental Retardation Protein FMRP in the DNA Damage Response, Cell. 2014 May 8;157(4):869-81. PMID: 24813610
- 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
- Brueckner, F., Armache, K. J., Cheung, A., Damsma, G. E., Kettenberger, H., Lehmann, E., Sydow, J., and Cramer, P. (2009) Structure-Function Studies of the RNA Polymerase II Elongation Complex, Acta Crystallogr D Biol Crystallogr 65, 112-120. PMID: 19171965
- Cramer, P., Armache, K. J., Baumli, S., Benkert, S., Brueckner, F., Buchen, C., Damsma, G. E., Dengl, S., Geiger, S. R., Jasiak, A. J., Jawhari, A., Jennebach, S., Kamenski, T., Kettenberger, H., Kuhn, C. D., Lehmann, E., Leike, K., Sydow, J. F., and Vannini, A. (2008) Structure of Eukaryotic RNA Polymerases, Annu Rev Biophys 37, 337-352. PMID: 18573085
- Jasiak, A. J*., Armache, K. J*., Martens, B., Jansen, R. P., and Cramer, P. (2006) Structural Biology of RNA Polymerase III: Subcomplex C17/25 X-Ray Structure and 11 Subunit Enzyme Model, Mol Cell 23, 71-81. * Equal contribution. PMID: 16818233
- 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
- Armache, K. J., Kettenberger, H., and Cramer, P. (2005) The Dynamic Machinery of mRNA Elongation, Curr Opin Struct Biol 15, 197-203. PMID: 13837179
- 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
- Kettenberger, H., Armache, K. J., and Cramer, P. (2003) Architecture of the RNA Polymerase II-TFIIS Complex and Implications for mRNA Cleavage, Cell 114, 347-357. PMID: 12914699
- 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