Faculty

The DNA of eukaryotes is packaged into chromatin by the wrapping of ~146 bp of DNA around a core histone octamer. This packaging serves to compact the DNA into the nucleus, but also presents a barrier to cellular processes, such as transcription, replication and repair, which require access to the DNA. Therefore, controlling access to the chromosomal DNA represents an important regulatory point for these processes. Two major classes of enzymes control access to chromatin. The first class includes enzymes that covalently modify the histones. Examples include acetyltransferases and deacetylases, methyltrasferases, kinases, and ubiquitin ligases. The second major class of enzymes uses the energy of ATP to alter the structure and/or location of the nucleosome. The targeting of these factors to chromatin determines the transcriptional output of a given gene. Control of these transcriptional events can subsequently coordinate cellular events such as apoptosis, proliferation, and differentiation. Disruption of these events is critical to many pathologies including neoplastic transformation and developmental disorders. Indeed, several genes encoding components of chromatin regulatory complexes have been implicated as etiologic agents in many cancers and hereditary malformations.

Projects in our laboratory focus on defining the mechanisms of higher eukaryotic gene regulation through the modification of chromatin structure. Importantly we want to discover how these pathways are linked to development and neoplastic transformation. One example is the connection between the Wnt signaling pathway that controls cell proliferation and fate by regulating transcriptional coactivators that convert a repressed gene to an active gene by reconfiguring chromatin structure. The Wnt/B-catenin signaling pathway performs a vital role in several developmental pathways and has also been shown to be involved in tumorigenesis, particularly colorectal cancers. We have identified a novel protein, CHR1, that can regulate Wnt/B-catenin mediated transcription by using the energy of ATP hydrolysis to alter chromatin structure. Therefore aberrant CHR1 chromatin remodeling activity could be a contributing factor to neoplastic transformation.

Representative Publications

1. Bochar, D.A., Pan, Z.Q., Knights, R., Fisher, R.P., Shilatifard, A. and Shiekhattar, R. "Inhibition of Transcription by the Trimeric Cyclin-dependent Kinase 7 Complex", J. Biol. Chem., 1999, 274, 13162.

2. Bochar, D.A., Savard, J., Wang, W., Lafleur, D.W., Moore, P., Cote, J. and Shiekhattar, R. "A Family of Chromatin Remodeling Factors Related to Williams Syndrome Transcription Factor", Proc. Natl. Acad. Sci. USA, 2000, 97, 1038.

3. Bochar, D.A., Wang, L., Beniya, H., Kinev, A., Xue, Y., Lane, W.S., Wang, W., Kashanchi, F. and Shiekhattar, R., "BRCA1 is Associated with a Human SWI/SNF-related Complex: Linking Chromatin Remodeling to Breast Cancer", Cell, 2000, 102, 257.

4. Marmorstein, L.Y., Kinev, A.V., Chan, G.K., Bochar, D.A., Beniya, H., Epstein, J.A., Yen, T.J. and Shiekhattar, R., "A Human BRCA2 Complex Containing a Structural DNA Binding Component Influences Cell Cycle Progression", Cell, 2001, 104, 247.

5. Bochar, D.A., Hakimi, M-A., Chonoweth, J., Lane, W.S., Mandel, G. and Shiekhattar, R., "A Core-BRAF35 Complex Containing Histone Deacetylase Mediates Repression of Neuronal-specific Genes", Proc. Natl. Acad. Sci. USA, 2002, 99, 7420.

6. Hakimi, M-A., Bochar, D.A., Schmiesing, J.A., Dong, Y., Barak, O.G., Speicher, D.W., Yokomori, K. and Shiekhattar, R., "A Chromatin Remodelling Complex that Loads Cohesin onto Human Chromosomes", Nature, 2002, 418, 994.