P53 Maintains Hepatic Cell Identity During Liver Regeneration

<p>p53 MAINTAINS HEPATIC CELL IDENTITY DURING LIVER REGENERATION</p> <p>Zeynep Hande Coban Akdemir, B.S.,M.A.</p> <p>Advisory Professor: Michelle Craig Barton, Ph.D.</p> <p>p53 is a tumor suppressor that has been well studied in tumor-derived, cultured cells. However, its functions in normal proliferating cells and tissues are generally overlooked. We propose that p53 functions during the G1-S transition can be studied in normal, differentiated cells during surgery-induced liver regeneration. Two-thirds partial hepatectomy (PH) of mouse liver offers a unique model to compare p53 functions in regenerating versus sham (control) cells. My <strong>hypothesis</strong> is that intersection of global expression analyses (microarray and RNA sequencing) and profiling of p53 interactions with chromatin (ChIP sequencing) at the G1-S transition of normal cell cycle, corresponding to 24h post-PH in mice liver regeneration, will reveal p53 functions during cell cycle regulation in normal cells and during tissue regeneration.</p> <p>Combining chromatin immunoprecipitation with next generation sequencing technology (ChIP-Seq) allowed detection of genome-wide binding of p53 to target genes in liver. We found 5074 <em>de novo </em>p53 target genes, 92% of which participate in non-canonical p53 functions, mainly developmental processes. Integration of ChIP-Seq findings with global expression profiling (RNA-Seq) of both normal and p53-null liver allowed us to identify functional p53 target genes. Intriguingly, our data analysis revealed that a specific subset of p53-activated target genes is involved in liver-enriched functions such as lipid biosynthetic process, steroid metabolic process, circadian rhythm, and drug detoxification. These findings suggested that the loss of p53-chromatin interactions in regenerating liver may result in a decreased activity of differentiation-specific cellular processes and in attenuation of hepatic cell identity. Remarkably, p53 cooperates with the master regulator of hepatocyte differentiation, HNF4α, to induce 78% of these genes, including a number of liver-enriched transcription factors such as CCAAT/enhancer binding protein beta (CEBPβ), hepatocyte nuclear factor 6 alpha (HNF6α), hepatocyte nuclear factor 6 beta (HNF6β). Thus, p53 acts in concert with HNF4α to promote the maintenance of liver functions during the G1àS transition of the cell cycle of normal proliferating livers cells.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2014

Author dc:creator

• Coban Akdemir, Zeynep Hande

Contributors dc:contributor

• Dr. Michelle Craig Barton
• Dr. Sharon R.Y. Dent
• Dr. Wei Li

• p53
• liver regeneration
• hepatic identity
• chromatin interactions
• gene expression
• genome-wide profiling
• HNF4α
• Bioinformatics
• Biology
• Computational Biology
• Developmental Biology
• Life Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/465

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1499