Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Edward E. Morrisey

Abstract

Lungs are complex organs comprising many and varied cell types with distinct and complementary functions. These myriad lineages arise during development from common progenitors through series of patterning cues and cell fate decisions. Epigenetic regulation of cell fate decisions is critical in many stem and progenitor cells and in the specification and appropriate development of many organs, but its role in lung development is largely unknown. In this work, I show that the Polycomb Repressive Complex 2 enzyme Ezh2 is required for lung development. I demonstrate that Ezh2 is highly expressed during early lung development and that expression diminishes late in development. Using conditional genetic deletion of Ezh2 in the lung endoderm and in the lung mesoderm in mice, I found that Ezh2 is required to suppress cell cycle inhibitors during lung development and allow proliferation and proper lung growth, alveolar development, and the capacity to breathe at birth. Gene expression, immunohistochemistry, and lineage tracing analyses show that Ezh2 in the endoderm suppresses the basal stem cell lineage and regulates the balance of basal cells and secretory club cells. Further conditional genetic deletions of Ezh2 in the basal cell and club cell lineages show that Ezh2 is not required to balance these cell types once they express mature lineage markers. Gene expression, immunohistochemistry, and lineage tracing analyses show that Ezh2 in the mesoderm suppresses ectopic smooth muscle development from the mesothelium. Conditional genetic deletion of Ezh2 in the mesothelium shows a mesothelial-specific requirement for Ezh2 to suppress the smooth muscle lineage. Chromatin analysis reveals that Ezh2 represses master transcription factors of the basal cell and smooth muscle lineages, thereby suppressing these lineages during lung development. These studies reveal a critical role for epigenetic transcriptional repression by Ezh2 to suppress ectopic lineages and allow normal lung development.

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