The Role of Variant Chromatin Remodeling Complexes in Chromatin State and Cancer Although all cells in the body contain the same DNA, variations in the patterns of expression give rise to a huge diversity of cell types. One way this process is regulated is by the physical structure of DNA. In cells, DNA is wrapped around proteins called histones to form chromatin. How tightly packaged this molecule is can have profound effects on gene expression. A family of proteins called chromatin remodeling complexes are capable of altering chromatin structure, allowing genes to be turned on or off. Large sequencing studies of many tumor types has identified numerous mutations in chromatin remodeling complexes. Because mutations in chromatin remodeling complexes are common in many types of cancer, understanding the changes in gene expression and chromatin structure that occur when one of these complexes is lost may provide insight towards the development of therapeutic strategies also common to many cancers. There are four families of chromatin remodeling complexes, and all perform the common duty of altering chromatin structure. It has recently been proposed that there is significant interactions between families of remodeling proteins, as well as interactions with other chromatin regulating proteins. The main goal of this proposal is to determine how loss of one type of chromatin remodeling complex affects the global state of chromatin and how these changes may drive a cell towards cancer. The SWI/SNF family of chromatin remodeler has many variant forms, and several of these variants are commonly mutated in hepatocellular carcinoma. Using this model system the above question will be addressed in three parts: 1.) Where do variant forms of the SWI/SNF chromatin remodeling complex function in the genome? 2.) What happens to gene expression and chromatin structure when a variant form of this complex is lost? 3.) What changes occur in the mouse liver when this complex is lost, and does loss lead to tumor formation? The SWI/SNF complex has primarily been studied as a single entity, but frequent mutations in several mutually exclusive subunits of this complex highlight the need for a better understanding of the many variant forms of the complex. Successful completion of this project will yield critical insights ino whether variant forms of a remodeling complex all function in the same way, or rather, if these complexes have more complicated interactions. Understanding this distinction will be critical for designing therapeutic strategies that target the chromatin state of a tumor cell.
Chromatin remodeling complexes are mutated in many cancers and developmental disorders. A mutation is normally only found in one type of remodeling complex, suggesting the remaining remodelers are still functional. This project addresses how the many forms of these remodeling complexes interact, both with the genome, and with each other. Understanding the interactions of these families of chromatin regulators will lead to critical insights about how the loss of a specific chromatin remodeling complex alters chromatin structure, gene expression, and contributes to tumor formation.
|Rothbart, Scott B; Dickson, Bradley M; Raab, Jesse R et al. (2015) An Interactive Database for the Assessment of Histone Antibody Specificity. Mol Cell 59:502-11|
|Raab, Jesse R; Resnick, Samuel; Magnuson, Terry (2015) Genome-Wide Transcriptional Regulation Mediated by Biochemically Distinct SWI/SNF Complexes. PLoS Genet 11:e1005748|