Investigator: Arnob Dutta, University of Rhode Island

Mentor: Niall Howlett, University of Rhode Island

Scientific Theme: Cancer

Abstract: Access to DNA packaged into chromatin is orchestrated by the function of large multi-subunit chromatin modifying complexes, which either post-translationally modify residues on histone tails or use ATP to slide/evict histones. Recent genome-wide profiling in diseased states has highlighted that somatic mutations in genes encoding subunits of chromatin modifying complexes are common drivers of tumorigenesis and diseases. However, the mechanistic implications of these mutations on the overall structure of chromatin modifying complexes and their bearing on altered transcriptional output remains poorly understood. The board aim of my research program is to gain mechanistic insight into functioning of large transcription regulating complexes, with focus on disease causing mutations. Among the ATP-dependent chromatin remodelers, the evolutionary conserved Swi/Snf complex, essential for gene expression of stress dependent genes in yeast and developmental genes in higher eukaryotes, is the founding member. Using ATP hydrolysis by the catalytic subunit (Snf2 in yeast; Smarca2/Smarca4 in humans), Swi/Snf disrupts histone:DNA contacts, resulting in sliding of the histone octamer on DNA or the eviction of histones. Swi/Snf targeting to genes is determined by interactions with sequence specific transcription factors and post-translational modification of histone tails. While yeast has one form of Swi/Snf, multiple human complexes exist, often with unique components and specialized roles in tissue and developmental specific gene regulation. Recent analyses of cancer genomes have highlighted that several hSwi/Snf subunits act as tumor suppressors, with a surprisingly high frequency of mutations, estimated at ~20% across cancer types. Interestingly these mutations are not restricted to the catalytic subunits but are often found in the accessory members of the complex as well. Since, a consequence of many of the mutations in cancers and other disease, is complete loss of subunit proteins themselves, it would be expected to alter the composition and in vivo protein interactions of the complex, resulting in altered functions of Swi/Snf leading to misregulation of gene transcription. Given that hSwi/Snf is critical for gene regulation of proteins involved in many cellular processes, targeting the complex itself may not be a feasible option. Thus, it is essential to understand the complex composition and specifically identify proteins that interact with mutant hSwi/Snf, providing for viable strategies for intervention in disease.

Human Health Relevance: Cancerous cells have unique transcriptional profiles. Since many cancer mutations occur in the cellular machinery that regulates expression of genes themselves, it is important to understand how these mutations affect composition and cellular-protein interactions of the mutated protein complexes, thereby affecting their roles in expression of genes. Understanding these mechanisms will help identify viable targets for intervention in disease.