Functional analysis of the histone variant H2A.Z during lineage commitment
Author(s)
Surface, Lauren E. (Lauren Elizabeth)
DownloadFull printable version (18.36Mb)
Other Contributors
Massachusetts Institute of Technology. Department of Biology.
Advisor
Laurie A. Boyer.
Terms of use
Metadata
Show full item recordAbstract
remained enigmatic. In this thesis, we dissect the role of H2A.Z during lineage commitment. In particular, we focused on the Polycomb-mediated mono-ubiquitylation of H2A.Z. We found that this modification regulates the differentiation potential of mouse embryonic stem cells (mESCs). Loss of H2A.Z ubiquitylation leads to a disrupted chromatin state and derepression of key developmental regulators in mESCs. Furthermore, we show that H2A.Zub is a crucial component required for regulating canonical Wnt signaling, a key pathway in early embryogenesis. Consistent with hyperactivation of Wnt signaling, ESCs lacking H2A.Zub fail to differentiate into neuronal lineages. Therefore, we suggest that modification of H2A.Z is crucial for the response to stimuli. Using quantitative proteomics, we uncovered a role for H2A.Z ubiquitylation in modulating the protein interaction landscape of H2A.Z. H2A.Zub impacts a specific subset of protein interactions. By investigating several of these differential interactions, we revealed a role for H2A.Zub in regulation of DNA methylation, the deposition of repressive histone modifications, as well as a potential connection between H2A.Zub and DNA damage. Therefore, ubiquitin may serve as a binding platform for subsequent recruitment of chromatin-associated factors. These data suggest a mechanism by which post-translation modification of H2A.Z can allow for rapid changes in cell state in a context dependent manner. On a broader level, our work contributes mechanistic insights into the essential requirement of H2A.Z across eukaryotes. Collectively, this work sets the stage for understanding how post-translation modifications can contribute to further specialization of H2A.Z in a context-dependent manner.
Description
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2014. This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. Page 126 blank. Cataloged from student-submitted PDF version of thesis. Includes bibliographical references.
Date issued
2014Department
Massachusetts Institute of Technology. Department of BiologyPublisher
Massachusetts Institute of Technology
Keywords
Biology.