Biomedical Sciences Graduate Program | University of California, San Francisco

Research in the Madhani lab can be divided into three areas.

1. Systematic genetic analysis of virulence in the human AIDS fungal pathogen Cryptococcus neoformans. C. neoformans is an encapsulated oppotunistic yeast pathogen of humans that causes 5-10% of the worldwide deaths from HIV/AIDS. The most common cause of death from C. neoformans infection is meningitis. The goal of our studies is to begin to approach the host-pathogen interactions by defining the complete set of genes required for virulence in a mammalian host. To date we have knocked out 20% of the nonessential genes of this pathogen (~1200 genes) and are assessing them in mice for defects in virulence. Completion of the knockout collection and virulence studies should yield a global picture of genes requires for pathogenesis and provide numerous entrees into the host-pathogen relationship of this important AIDS pathogen. In addition, we are using whole-genome transcriptional profiling as a supplementary tool to probe the circuitry of the genome as it relates to virulence.

2. Molecular Biology of Euchromatin in Saccharomyces cerevisiae We have found that euchromatin is not a default state that is acted upon by gene silencing mechanism. Rather, euchromatin contains factors analogous to silencing factors that antagonize epigenetic switching to the opposite state. These include the unviersally conserved histone variant H2A.Z and several conserved histone methylations. Current work focuses on how these are targetted to euchromatin and the mechanisms by which they act to antagonize heterochromatin formation. This work should lead to a better understanding of how cells switch between epigenetic states which is important for understanding normal development and abnormal gene silencing in tumors.

3. Specificity of MAP Kinase Signaling in Saccharomyces cerevisiae A central question in cell biology is how cells use the same signal transduction components to signal distinct responses to different inputs. For example, in Saccharomyces cerevisiae, a shared set of MAP kinase signaling components transduce the mating pheromone signal as well as a signal that controls filamentous growth. Despite this sharing of components, pheromone treatment of cells does not normally induce genes involved in filamentous growth. We have found that two mechanism suppress erroneous cross-talk between these two pathways. First, a scaffold protein called Ste5 biases pheromone signaling towards the activation of the mating-specific MAP kinase Fus3. Second, Fus3 phosphorylates and induces the degradation of the transcription factor that lies at the terminus of the filamentous growth pathway, Tec1. Current work focuses on understanding the mechanism by which the rate of Tec1 degradation is matched to the rate of spillover at higher levels in the pathway, how the mating and filamentous growth pathway are insulated from the HOG pathway that also shares components with these pathway, and the mechanism by which the scaffold protein Ste5 functions to suppress cross-talk.