Our cells contain about 2 meters (6 feet) of DNA packaged into a nucleus only 10 micrometers wide or ten times thinner than the width of a human hair. This compaction is possible because eukaryotic DNA is packaged as chromatin by wrapping the DNA around a core of histone proteins into the nucleosome. Thus, if we are to understand how genes are turned on or off in our cells, we need to understand not just how our DNA genetic material is recognized by proteins, but how the nucleosome complex of DNA and histones is recognized. Despite the numerous chromatin enzymes discovered in the last 15 years, our understanding of how these enzymes interact with the nucleosome is limited.
We have determined the crystal structure of the Polycomb PRC1 ubiquitylation module in complex with the nucleosome. This is the first atomic structure of a chromatin enzyme/nucleosome complex and the first structure of a ubiquitin E2/E3 complex bound to its substrate. The structure shows how an epigenetic chromatini enzyme can achieve substrate specificity through recognition of the nucleosome architecture instead of through local recognition of a histone tail peptide.
Our structure of the LSD1 histone demethylase in complex with its corepessor protein, CoREST, and the nucleosome shows how CoREST enables LSD1 to act on nucleosome substrates. LSD1 does not contact the nucleosome core particle but instead binds to extranucleosomal or linker DNA outside the nucleosome core. CoREST makes critical contacts to the nucleosome core and to extranucleosomal DNA, and thus directs LSD1 to nucleosomes.
Current chromatin enzyme projects include other epigenetic chromatin modification enzymes which introduce post-translational modifications into the histone components of chromatin including histone acetyltransferase, methyltransferase and ubiquitin ligase complexes. Our goal is to provide mechanistic understandings of these and other chromatin enzyme-nucleosome complexes through biochemical studies and atomic resolution crystal structures.
Pointers to articles in the popular press, podcasts and review articles about chromatin and chromatin modifications can be found in the background reading section.
- Kim, S., J. Zhu, N. Yennawar, P. Eek and S. Tan (2020) Crystal structure of the LSD1/CoREST histone demethylase bound to its nucleosome substrate, Mol. Cell. (abstract)
- Sun, J., Paduch, M., Kim, S., Kramer, R.M., Barrios, A.F., Lu, V., Luke, J., Usatyuk, S., Kossakoff, A.A and Tan. S. (2018) Structural basis for activation of SAGA histone acetyltransferase Gcn5 by partner subunit Ada2, PNAS. (abstract)
- McGinty, R.K., R.D. Makde and S. Tan (2016). Preparation, crystallization, and structure determination of chromatin enzyme/nucleosome complexes, Method Enzymol, 573:43-65. (abstract).
- Girish, T.S., R.K. McGinty and S. Tan (2016). Multivalent interactions by the Set8 histone methyltransferase with its nucleosome substrate, J. Mol Biol., 428:1531-1543. (abstract)
- McGinty, R.K. and S. Tan (2016) Recognition of the nucleosome by chromatin factors and enzymes, Curr. Opin. Struct. Biol., 21:128-136.
- Kim, S., N. Cahtterjee, M.J. Jennings, B. Bartholomew, and S. Tan (2015). Extranucleosomal DNA enhances the activity of the LSD1/CoREST histone demetthylase complex. Nucl. Acid Research, 43:4868-4880. (abstract) (pdf link, 6.1 MB)
- McGinty, R.K, and S. Tan (2015). Nucleosome Structure and Function. Chem Reviews, 115:2255-2273.
- McGinty, R.K, Henrici, R.C. and S. Tan (2014). Crystal structure of the PRC1 ubiquitylation module bound to the nucleosome. Nature, 514:591-596.
- McGinty, R.K. and S. Tan (2014). Histones, Nucleosomes, and Chromatin Structure. In Fundamentals of Chromatin, J.L. Workman and S.M. Abmayr, ed (New York: Springer).
- Makde, R.D. and S. Tan (2013). Strategies for crystallizing a chromatin protein in complex with the nucleosome core particle. Anal. Biochem., 442:138-145 (abstract).
- Huang, J and S. Tan (2013). Piccolo NuA4-Catalyzed Acetylation of Nucleosomal Histones: Critical Roles of an Esa1 Tudor/Chromo Barrel Loop and an Epl1 Enhancer of Polycomb A (EPcA) Basic Region. Mol. Cell. Bio. , 33:159-169. (abstract)
- Chittuluru, J.R., Y. Chaban, J. Monnet-Saksouk, M. J. Carrozza, V. Sapountzi, W. Selleck, J. Huang, M. Cramet, S. Allard, G. Cai1, J. L. Workman, M.J. Fried, S. Tan, J. Cote and F. J. Asturias (2011). Structure and nucleosome interaction of the NuA4 and Piccolo-NuA4 histone acetyltransferase complexes. Nature Str. Mol. Biol., 39:8378-8391. (abstract)
- Makde, R.D., J.R. England, H. Yennawar and S. Tan (2010). Structure of RCC1 chromatin factor bound to the nucleosome core particle. Nature, 467:562-566. (abstract)
- England, J.R., J. Huang, M.J. Jennings, R. D. Makde, and S. Tan (2010). RCC1 uses a conformationally diverse loop region to interact with the nucleosome: a model for the RCC1-nucleosome complex. J. Mol Biol., 398:518-529. (abstract)