Author ORCID Identifier
https://orcid.org/0000-0003-1755-6454
Date of Graduation
5-2019
Document Type
Dissertation (PhD)
Program Affiliation
Genes and Development
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Elsa Flores, PhD
Committee Member
Min Gyu Lee, PhD
Committee Member
Russell Broaddus, MD, PhD
Committee Member
Jichao Chen, PhD
Committee Member
Jonathan Kurie, MD
Abstract
Cell of origin studies have determined separate populations of lung progenitor cells that give rise to lung adenocarcinoma and squamous cell carcinoma. ΔNp63 is known to regulate lung development but its role in lung cancer progression remains unclear. We utilized a ΔNp63-specific conditional knockout mouse model to determine ΔNp63’s role in lung progenitor cells and lung cancer. In vivo and in vitro experiments revealed a role for ΔNp63 in maintaining lung progenitor cells. ChIP-seq results indicate that deletion of ΔNp63 results in robust loss of enhancer histone marks at cell identity genes for lung progenitor populations of basal cells and AT2 cells. Analysis of ΔNp63-regulated pathways uncovered that ΔNp63 regulates cell-type-specific genes as well as common genes for basal cells and AT2 cells. Our experiments using a deactivated cas9 system showed that co-targeting of ΔNp63 and the enhancer activator p300 to p63 binding motifs significantly enhanced the transcription of ΔNp63-regulated genes, indicating that ΔNp63 directly regulates enhancer region activity. These novel findings suggest that ΔNp63 acts as a master regulator of transcriptional and epigenetic networks in lung progenitor cells whose oncogenic characteristics are essential to the initiation and progression of lung cancer.
Keywords
ΔNp63, NSCLC, Lung squamous cell carcinoma, Lung adenocarcinoma, Super-enhancers, Basal cells, Alveolar type 2 (AT2) cells, bronchioalveolar stem cells (BASCs), Lung stem cells, Low cell number ChIP-seq