Histone post-translational modifications (PTMs) can alter the biophysical properties of chromatin and the binding of effector proteins, thereby regulating biological processes including transcription, mitotic chromosome compaction and segregation, and repair of DNA damage. A fundamental challenge in chromatin research is to understand the mechanisms by which combinations of PTMs regulate chromatin processes. The study of histone phosphorylation, a highly charged PTM with great potential to modulate histone-regulated processes, is the focus of this research. The overall goal of the proposed research plan is to apply state of the art and novel experimental approaches to understand the role of histone phosphorylation in the regulation of chromatin processes in cell cycle progression and transcriptional regulation. During the training period I will characterize combinations of histone PTMs, with histone phosphorylation as a predicted regulatory switch, and through the training period and into the independent phase of my career, I will study their role in diverse biological processes. While histone phosphorylation has long been correlated with immediate-early gene activation, mechanistic understanding of the role of phosphorylation in the rapid transcription response is lacking. With the development of new tools, and importantly, with the training that I describe during the mentored period, my proposed research promises to apply diverse approaches to reveal new insights into the rapid recruitment and activity of transcription machinery at genes decorated by newly phosphorylated histones. Finally, through the combination of computational and comparative genomics techniques and biochemical approaches that I will master during the training period, I propose to study, into the independent phase of my career, the broader mechanisms and evolution of the rapid transcription response, using as a guide the regulatory DNA elements that are associated with histone phosphorylation upon stimulation. Histone phosphorylation, with its distinct biophysical properties and potential to dramatically alter histone-reader molecular interactions, is a principal mechanism for the transduction of environmental signals to chromatin with consequences in diverse biological processes.
The identity of cell types-such as neurons, activated immune cells, or tumor cells-is controlled by variances in how the DNA is packaged into 'chromatin' and regulated. These studies aim to reveal how environmental signals are transmitted to chromatin to induce changes in gene expression during cell division, cellular development, responses to inflammation, and the conversion of normal cells to tumor cells.
