The Role of Master Epigenetic Regulators in Ocular Chemical Injury

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The Role of Master Epigenetic Regulators in Ocular Chemical Injury SUMMARY Mustard vesicants including sulfur mustard (SM) and nitrogen mustard (NM) cause severe respiratory, skin, and ocular injuries. They have been used as a chemical weapon in the warfare and also impose a potential threat to civilians as they could be used by the terrorists' attack. Ocular injuries in particular corneal injury were prevalent in SM-exposed victims. Inflammation, neovascularization and fibrosis are three major problems and players in mustard-induced corneal injury, yet the underlying mechanisms are largely unknown, which limits the development of effective managements for the disease. The BET (bromodomain and extra-terminal domain) family proteins, including universally expressed BRD2, BRD3 and BRD4 and testis-specific BRDt, are epigenetic readers. They recognize and bind to acetylated lysine (KAc) within the N-terminal tail protruding from the histone core of the nucleosome, and act as scaffold proteins to recruit transcription factors and the positive transcription elongation factor b (P-TEFb) complex, which phosphorylates and releases paused RNA polymerase II (RNAPII) to transcript the transcription factor-targeted genes. The BETs play a key role in inflammation, neovascularization and fibrosis in many disease but their role in ocular chemical injury is unknown. We now provide compelling evidence suggesting that BETs have a key role in corneal mustard injury and propose to further explore this novel mechanism. We will test the hypothesis that NM injury induces corneal inflammation, neovascularization and fibrosis via activation of master epigenetic regulator BETs using mouse and rabbit models, selective BTE inhibitors, state of the art in vivo ocular imaging techniques including optical coherence tomography (AS-OCT) and OCT-angiography (OCT-A), and genomic profiling and immunohistochemistry approaches. The proposed work will allow us to define the role of BETs in mustard- induced injury by characterizing the contributions of BD1 and BD2 in corneal injury, elucidating the underlying mechanisms, and testing whether BET inhibition could effectively treat acute and delayed injury. Considering the success that has been reported in developing BET blockers with acceptable safety profiles and promising efficacy in several phase I and II clinical trials, BET inhibitors may offer high translational potentials for being tested and eventually used in clinical studies.