Investigating The Role of The P63 Isoform Δnp63 In Lung Stem Cell Populations and Lung Cancer

<p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2019

Authors dc:creator

• Wu, Sarah J
• <p>https://orcid.org/0000-0003-1755-6454</p>

Contributors dc:contributor

• Elsa Flores, PhD
• Min Gyu Lee, PhD
• Russell Broaddus, MD, PhD

• 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
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/931

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1977