Michael Cosgrove, PhD

RESEARCH ABSTRACT

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 drug 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, enzyme kinetics and rational drug design.

For more information see: http://www.cosgrovelab.org

Selected references:

Kobrossy, L., Wu, W., Zhang, C., Turner, C.E., and Cosgrove, M.S.