AEBP2 is a zinc finger protein that has been shown to interact with the mammalian Polycomb Repression Complex 2 (PRC2). I characterized this unknown protein and tested its potential targeting roles for the PRC2. AEBP2 is an evolutionarily well-conserved gene that is found in animals ranging from flying insects to mammals. The transcription of mammalian AEBP2 is driven by two alternative promoters and produces multiple transcripts that give rise to at least two isoforms of the protein. These isoforms show developmental stage-specific expression patterns: the larger adult-specific form (52 kDa) and the smaller embryo-specific form (31 kDa). The AEBP2 protein binds to a DNA-binding motif with an unusual bipartite structure, CTT(N)15-23cagGCC with lower-case base pairs being less critical. A large fraction of AEBP2's target loci also map closely to the known target loci of the PRC2. In fact, many of these loci are co-occupied by the two proteins, AEBP2 and SUZ12. This suggests that AEBP2 is most likely a targeting protein for the mammalian PRC2 complex. To investigate the in vivo roles of this protein, a mutant mouse line with disrupted Aebp2 transcription has been generated. Breeding experiments demonstrated embryonic lethality in the Aebp2-mutant homozygotes, but survival of the heterozygotes to adulthood with fertility. In developing mouse embryos, Aebp2 is expressed mainly within cells of neural crest origin, such as the dorsal root ganglia, and facial cartilages and bones. In addition, many heterozygotes display a set of phenotypes, including enlarged colon and hypopigmentation, similar to those observed in human patients with Hirschsprungs disease and Waardenburg syndrome. These phenotypes are caused by the absence of the neural crest-derived ganglia in hindguts and melanocytes. Additional analyses further confirmed changes in the expression and methylation levels of H3K27me3 on the genes involved in the development of the neural crest cells in the Aebp2 heterozygotes. Overall, these results suggest that Aebp2 may regulate the development of the neural crest cells through the PRC2-mediated epigenetic mechanism.
| Identifer | oai:union.ndltd.org:LSU/oai:etd.lsu.edu:etd-11122010-182021 |
| Date | 17 November 2010 |
| Creators | Kim, Hana |
| Contributors | Li, Shisheng, DiMario, Patrick, Donze, David, Batzer, Mark, Kim, Joomyeong |
| Publisher | LSU |
| Source Sets | Louisiana State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lsu.edu/docs/available/etd-11122010-182021/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached herein a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to LSU or its agents the non-exclusive license to archive and make accessible, under the conditions specified below and in appropriate University policies, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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