Defining PRC2 complex epigenomic control in alveolar progenitor cells

PROJECT SUMMARY The alveolar region of the mammalian lung is a complex, precisely structured tissue required for the primary functions of the respiratory system, gas exchange and tissue oxygenation. Damage to the alveolar epithelium plays a central role in human lung diseases including Acute Respiratory Distress Syndrome (ARDS), a prevalent, high impact clinical disorder that affects up to 5% of mechanically ventilated patients in the developed world. The mortality rate of ARDS approaches 40%, and the recovery for ARDS survivors is arduous, with a substantial burden of multi-system disability continuing 5 or more years following hospitalization. Critically, while many ARDS survivors recover lung function, a subset of patients develops persistently abnormal pulmonary function, imaging evidence of pulmonary scarring, and pulmonary symptoms even years after ARDS. To date, no data exists regarding the mechanisms that guide ARDS recovery. These challenges have been made more acute by the coronavirus pandemic, which has exposed a large proportion of the human population to acute lung injury. An enormous population of patients is at risk of both acute and chronic lung consequences of lung injury following coronavirus infection, emphasizing the clear and urgent need for new regenerative therapies to promote recovery from acute lung disease. Regeneration in many organs is driven by adult facultative progenitor cells. We recently discovered a facultative progenitor cell in the mouse and human lung which participates in regeneration after viral injury we call alveolar epithelial progenitors (AEPs). Progenitor cells control their chromatin carefully, as they must maintain more broad potential than fully differentiated cells, and so a hallmark of progenitor chromatin state is regions of active regulation between fully open and fully closed states, so called poised chromatin. Unique preliminary data from our laboratory and review of the literature support the idea that the chromatin modifying complex PRC2 is a critical regulator of the progenitor chromatin state of AEPs. In this application, using a combination of advanced lung organoids and genetic mouse injury models, we will identify the temporal and functional requirements for PRC2 function in lung progenitors, define the key binding partners and targets of the PRC2 complex in maintenance of AEP progenitor state, and evaluate the genomic loci regulated by PRC2 complex activity necessary for AEP-mediated alveolar regeneration. Understanding these fundamental mechanisms will provide the framework needed to understand alveolar regenerative biology at a granular level and develop therapeutic strategies to maintain and restore AT2 progenitor function to drive repair following infection and environmental stress.