Carcinogen Susceptibility
We are examining mechanisms of carcinogen susceptibility, which is the tendency to accumulate DNA lesions (i.e. DNA adducts) upon exposure to exogenous carcinogens. Despite the unquestionable contribution of carcinogen-induced mutagenesis to cancer, the relationship between carcinogen susceptibility and mutation has not been previously explored. Indeed, factors that regulate localized genomic carcinogen susceptibility have profound consequences in carcinogenesis by defining probabilities for mutation; thereby causing disparities throughout the genome that can impact genome stability and disease.
Carcinogen susceptibility is regulated by genome architecture and predicts cancer mutagenesis
Genome‐wide mapping of UV‐induced DNA lesions in primary cells reveals strong correlations with melanoma mutation frequencies and with nuclear genome architecture, suggesting that peripheral repeat regions absorb UV damage to protect euchromatin.
Chromatin-Regulated metabolic stability
We are investigating how chromatin modifiers coordinate metabolic homeostasis. The coordination of cellular function with the metabolic environment is essential for adaptation and survival. Failure to adapt can lead to cell death, developmental defects, and disease. Indeed, energy metabolism alterations are a major contributing factor for many pathologies, including cancer, cardiovascular disease, and diabetes, which together account for half of all deaths in most industrialized societies.
Adaptive cellular responses are often achieved by rapid inducible changes in gene expression programs. An ideal mechanism to achieve this is through modification of chromatin. Indeed, changes in chromatin architecture are known to regulate inducible gene expression in response to intra- and extracellular signals. Despite this knowledge, the mechanisms by which chromatin modification contributes to metabolic plasticity remain largely unexplored.
Recognition of Histone Crotonylation by Taf14 Links Metabolic State to Gene Expression
Intermediary metabolites serve as co-factors for histone-modifying enzymes during metabolic flux, yet how these modifications contribute to transcriptional responses is poorly understood. Our findings expose an unexpected link between metabolic flux and transcription and demonstrate that histone crotonylation and Taf14 participate in the repression of energy-demanding gene expression.
INO80 Chromatin-Remodeling Coordinates Metabolic Homeostasis with Cell Division
The INO80 chromatin-remodeling complex is needed to coordinate cell division with nutrient availability in S. cerevisiae. In metabolically synchronized INO80 mutants, oscillations of metabolic gene expression and chromatin accessibility are severely attenuated.
The INO80 Chromatin Remodeler Sustains Metabolic Stability by Promoting TOR Signaling and Regulating Histone Acetylation
We performed an extensive genetic screen in S. cerevisiae in order to identify chromatin regulators of cellular metabolism. We found that the INO80 chromatin-remodeling complex is needed to enact TORC1-mediated transcriptional responses.
Endothelial Deletion of Ino80 Disrupts Coronary Angiogenesis and Causes Congenital Heart Disease
Deletion of the Ino80 chromatin remodeler in vascular endothelial cells results in defective coronary vascularization and heart muscle development that resembles the congenital heart disease of left ventricular non-compaction (LVNC).
The INO80 Complex Regulates Energy Metabolism
Genomic analysis reveal that INO80 regulates approximately 15% of transcripts in yeast, many of which are enriched in energy metabolism pathways. Specifically, INO80 mutants have increased expression of genes in the oxidative phosphorylation pathway, concomitant with elevated mitochondrial potential and oxygen consumption.