Class I Histone Deacetylases in Lung Development and Regeneration

The generation and development of the mammalian lung requires an elegantly regulated molecular program to control cell number, lineage specification, as well as morphogenetic remodeling. Histone deacetylases (HDACs) are a group of critical epigenetic factors that can mediate genome-wide transcriptional repression. However, the functional roles of HDACs in lung development and regeneration have not been previously characterized. In my dissertation, I utilized a series of mouse genetic models, ex vivo and in vitro assays to determine the functions of three members of class I HDAC family, HDAC1, HDAC2 and HDAC3 in lung epithelial development and regeneration. These studies reveal that HDAC1 and HDAC2 are redundantly required for the development and regeneration of Sox2+ proximal lung endoderm progenitors via regulation of Bmp4 and cell cycle inhibitors, while HDAC3 is critical for the alveolar epithelial remodeling and spreading during lung sacculation and alveologenesis. These findings demonstrate strong evidence for the crucial contributions of HDACs to lung development and regeneration, and provide novel insights into potential therapeutic directions for human lung diseases.