Michael Cosgrove, PhD
- Associate Professor of Biochemistry and Molecular Biology
Research Programs and Affiliations
- Biochemistry and Molecular Biology
- Biomedical Sciences Program
- Cancer Research Institute
Epigenetic regulation of chromatin, Mixed Lineage Leukemia, structural biology, enzymology.
Structural Biology of Chromatin, Epigenetics
The fundamental repeating unit of chromatin, the nucleosome, is composed of a disc-shaped octamer of histone proteins around which is wrapped approximately 150-base pairs of genomic DNA. Nucleosomes regulate access to genes by forming a steric block to transcription factors and RNA polymerase. Less clear is how nucleosome positioning on DNA is regulated. Recent studies show that nucleosomes are strategically positioned throughout genomes, and that even subtle changes in nucleosome positioning can have profound effects on gene expression. These results raise the possibility that alterations in nucleosome positioning could result in heritable silencing of genes, and the generation of new forms and functions at the organismal level. Such alterations are independent of changes in DNA sequence (i.e., epigenetic alterations) and may be another source of variation acted upon by natural selection. An understanding of this process requires an understanding of how cells encode nucleosome positioning information, and how that information is inherited. The keys to this process are the evolutionarily conserved histone proteins, the building blocks of nucleosomes; which, like DNA, are semi-conserved during DNA replication. Posttranslational modifications of histones provide a potential vehicle for the heritable transmission of epigenetic traits. Understanding how this process works is one of the central questions in biology today.
We are working to understand the molecular mechanisms that regulate methylation of histone H3 lysine 4 (H3K4), an epigenetic mark required for inheritance of transcriptionally active states of chromatin. In humans, H3K4 methylation is catalyzed by the Mixed Lineage Leukemia (MLL) group of enzymes, mutations of which are associated with leukemias, solid tumors, and developmental abnormalities. We use the tools of structural biology, biochemistry and biophysics to understand the molecular mechanisms for how the family of MLL enzymes work. We place an emphasis on understanding MLL’s function within the context of a large multi-subunit complex, called the MLL1 core complex. We have discovered that one of the components the MLL1 core complex is a novel histone methyltransferase we call WRAD, that catalyzes dimethylation within the complex. This finding changes the paradigm for our understanding of how multiple methylation is regulated within cells, which has profound implications for control of gene expression. Our studies on the structure and enzymology of MLL family enzymes will provide insights into their roles in cancer and developmental disorders, and provide the basis for the rational development of new treatments to help alleviate human suffering.
Projects are available to study the structure and enzymology of MLL family enzymes and the proteins with which they interact, using techniques such as X-ray crystallography, small angle X-ray scattering, analytical ultracentrifugation and enzyme kinetics.
Patel, A., Vought, V., Dharmarajan, V., and Cosgrove, M.S. (2011). A novel non-SET domain multi-subunit methyltransferase required for sequential nucleosomal histone H3 methylation by the MLL1 core complex. Journal of Biological Chemistry 286, 3359-3369.
Patel, A., Dharmarajan, V., Vought, V.E., and Cosgrove, M.S. (2009). On the mechanism of multiple lysine methylation by the human Mixed Lineage Leukemia protein-1 (MLL1) core complex. Journal of Biological Chemistry 284, 24242-24256. (Selected as JBC’s Paper of the Week).
Patel, A., Dharmarajan, V., and Cosgrove, M.S. (2008). Structure of WDR5 bound to Mixed Lineage Leukemia Protein-1 peptide. Journal of Biological Chemistry 283, 32158-32161. (Accelerated Publication, Featured on the journal cover).
Patel, A., Vought, V.E., Dharmarajan, V., and Cosgrove, M.S. (2008). A conserved arginine containing motif crucial for the assembly and enzymatic activity of the Mixed Lineage Leukemia protein-1 core complex. Journal of Biological Chemistry 283, 32162-32175. (Featured on the journal cover).
Cosgrove, M.S., Boeke, J.D., and Wolberger, C. (2004). Regulated nucleosome mobility and the histone code. Nature Structural & Molecular Biology 11, 1037-1043. (Highlighted on the Nature Milestones Gene Expression website).
Electron Microscopy reconstruction of the yeast vacuolar ATPase. Ribbon models for individual protein subunits have been fit to the electron density.
From the lab of Stephan Wilkens, PhD.