Author ORCID Identifier
0000-0002-2080-5450
Date of Graduation
5-2023
Document Type
Dissertation (PhD)
Program Affiliation
Genes and Development
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Guillermina Lozano
Committee Member
Richard Behringer
Committee Member
Anirban Maitra
Committee Member
Min Gyu Lee
Committee Member
Jichao Chen
Abstract
Death domain-associated protein 6 (Daxx) is a histone chaperone specific to Histone 3.3 (H3.3). DAXX interacts with ATRX forming a chromatin remodeling complex, which deposits H3.3 into telomeric and pericentric region of the genome. The importance of Daxx was manifested in embryonic development. The loss of Daxx leads to early lethality in mouse embryos around E6.5. Moreover, sequencing studies have revealed the importance of DAXX in human tumors. Mutually exclusive mutations in DAXX and ATRX occur in about 30% of pancreatic neuroendocrine tumors (PanNETs). Although lots of progress has been made in studying functions of DAXX, we still do not fully understand how DAXX functions as tumor suppressor in PanNETS and what functions of Daxx are essential for early embryonic development. To address these questions, we used genetically engineered mouse models to evaluate the tumor suppressor functions of Daxx in the mouse pancreas. Overall, our data suggest that Daxx is not robust tumor suppressor in the endocrine pancreas of mice and suggest the context of a human genome is essential for tumorigenesis. I also developed two Daxx mutant alleles in the mouse germline which abolish the interactions between Daxx and Atrx (DaxxY130A), and Daxx and H3.3 (DaxxS226A). I found that the interaction between Daxx and Atrx is dispensable for viability in both pre- and post-natal mice as homozygous Daxx-Y130A mutants are both viable and fertile. The loss of the Atrx interaction, however, does cause dysregulated expression endogenous retroviruses. On the contrary, the interaction between Daxx and H3.3 is not required for embryonic development but is essential for postnatal viability. Transcriptome analysis of embryonic tissues demonstrates that this interaction is important for silencing endogenous retroviruses and for maintaining proper immune cell composition. Combined, this study extends our understanding in Daxx functions.
Keywords
Daxx, Histone 3.3, Mouse Genetics, Pancreatic neuroendocrine tumor, Embryonic development