565B Morrill Hall
Office: (217) 244-4896
Lab: (217) 265-6439
Fax: (217) 244-1648
Mail to: Dept. of Cell and Developmental Biology
University of Illinois
601 S. Goodwin Avenue
Urbana, IL 61801
Associate Professor of Cell and Developmental Biology
Chromatin Structure, Protein-Nucleic Acid Interactions, Regulation of Gene Expression
B.Sc. Hons., University of Western Ontario (Biology)
M.Sc., University of Toronto (Physiology)
Ph.D., University of Toronto (Physiology)
Postdoc., University of Virginia
Chromatin structure, function and metabolism. Roles of histone modifications and other epigenetic factors in normal development and disease.
Every cell of your body contains at least one copy of your genome, comprised by more than 109 base pairs of DNA that would span over 2 meters (6 feet) if linearized. This DNA is wrapped around proteins and highly folded upon itself in a polymer referred to as chromatin (Fig. 1). The DNA-protein interactions in chromatin are necessary to package the genome into the microscopic confines of cell nuclei that are typically less than 5 microns in diameter. However, this imposes a requirement that portions of chromatin can be unfolded to allow gene transcription and other DNA-templated processes to occur. Moreover, the mechanisms governing chromatin condensation/decondensation must be regulated and reversible so that the degree of folding/unfolding of specific loci can be adjusted to match the differences in metabolic demand that exist between different cell types or in cells under different conditions. Conversely, global chromatin folding must be enhanced during cell division to properly form the highly condensed chromosomes that allow replicated genomes to be distributed equally among daughter cells.
Acetylation, methylation, phosphorylation and other post-translational modifications of histones, the most abundant proteins in chromatin, play key roles in modulating chromatin folding to regulate the accessibility of DNA for transcription, replication, recombination and repair. My group works to understand the molecular basis for how histone modifications change chromatin structure, and how the levels and genomic distributions of specific modifications are regulated to provide chromatin responses to physiological stimuli like hormones and growth factors. We also investigate the mechanisms by which aberrant histone modifications act as epigenetic factors in the pathogenesis of diseases including cancer. We use a wide range of contemporary techniques in biochemistry, cell and molecular biology to analyse model systems ranging from yeast to human cancer cells.
Two current focuses in the lab are:
Methylation of histone H4 at lysine 20. Mono-, di- and trimethylation at lysine 20 of H4 in animal cells was first discovered nearly 40 years ago, but little evidence about the functions of these modifications was available until recently. Unexpectedly, my students and I discovered that K20 dimethylation is one of the most abundant of all histone modifications, and that it serves as a platform for the targeted assembly of DNA damage response proteins into foci which initiate the repair of DNA double strand breaks (Fig. 2). We established that an enzyme known as Suv4-20 is responsible for forming most, if not all, dimethyl and trimethylK20-H4 in higher eukaryotes whereas PR-Set7 mediates the majority of K20 monomethylation. Now we are investigating the roles of K20 methylation in the structure and function of heterochromatin, and whether aberrant K20 methylation contributes to oncogenesis.
Histone H1 phosphorylation. The regulation and function of H1 phosphorylation has remained enigmatic since the discovery more than 30 years ago that the abundance and stoichiometry of H1 phosphorylation increases during cell cycle progression in animal cells. H1 phosphorylation is expected to promote chromatin decondensation and enhance DNA accessibility for transcription and other processes. Paradoxically, H1 hyperphosphorylation in vivo correlates with chromosome condensation and transcriptional repression during mitosis, but few details about the nature of H1 phosphorylation during interphase and mitosis are known. We have discovered that H1 phosphorylation sites in human cells are phosphorylated either exclusively during mitosis (M sites) or in both interphase and mitosis (I sites). Interphase H1 phosphorylation is hierarchical, strikingly homogenous, and associated with transcription by RNA polymerases I and II (Fig. 3). We are investigating how I-site phosphorylation facilitates gene expression, and how the levels and genomic distributions of interphase phosphorylated H1 are regulated in the contexts of normal cell growth and the deregulated growth of cancer cells.
Opportunities to perform graduate or post-doctoral work on these and other projects become available routinely so please e-mail email@example.com if you are interested.
Mizzen, C.A. (2004). Purification and analyses of histone H1 variants and H1 post-translational modifications. Meth. Enzymol. 375: 278-97.
Thomas, C.E., Kelleher, N.L., and Mizzen, C.A. (2006). Mass Spectrometric Characterization of Human Histone H3: A Bird’s Eye View. J. Proteome Res. 5: 240-247.
Wang, Y., Jorda, M., Jones, P.L., Maleszka, R., Ling, X., Robertson, H.M., Mizzen, C.A., Peinado M.A., and Robinson, G.E. (2006). Functional CpG Methylation System in a Social Insect. Science 314: 645-647.
Garcia, B.A., Pesavento, J.J., Mizzen, C.A., and Kelleher, N.L. (2007). Pervasive Combinatorial Modification of Histone H3 in Human Cells. Nat. Methods 4: 487-489.
Pesavento, J.J., Garcia, B.A., Streeky, J.A., Kelleher, N.L., and Mizzen, C.A. (2007). Mild Performic Acid Oxidation Enhances Chromatographic and Top Down Mass Spectrometric Analyses of Histones. Mol. Cell. Proteomics 6: 1510-1526.
Pesavento, J.J., Yang, H., Kelleher, N.L., and Mizzen, C.A. (2008). Certain and Progressive Methylation of Histone H4 at Lysine 20 During the Cell Cycle. Mol. Cell. Biol. 28: 468-486.
Yang, H., Pesavento, J.J., Starnes, T., Cryderman, D.E., Wallrath, L.L., Kelleher, N.L., and Mizzen, C.A. (2008). Preferential dimethylation of histone H4-Lys20 by Suv4-20. J. Biol. Chem. 283: 12085-12092.
Garcia, B.A., Thomas, C.E., Kelleher, N.L., and Mizzen, C.A. (2008). Tissue-specific expression and post-translational modification of histone H3 variants. J. Proteome Res. 7: 4225-4236.
Yang, H., and Mizzen, C.A. (2009). The multiple facets of histone H4-lysine 20 methylation. Biochem. Cell Biol. 87: 151-161.
Zheng, Y., John, S., Pesavento, J.J., Schultz-Norton, J.R., Schiltz, R.L., Baek, S., Nardulli, A.M., Hager, G.L., Kelleher, N.L., and Mizzen, C.A. (2010). Histone H1 Phosphorylation is Associated with Transcription by RNA Polymerases I and II. J. Cell Biol. 189: 407-415.