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dc.contributor.advisorTucker, Philip W.en
dc.creatorBrown, Mark Alan, 1975-en
dc.date.accessioned2008-08-28T23:33:19Zen
dc.date.available2008-08-28T23:33:19Zen
dc.date.issued2007-08en
dc.identifierb68792803en
dc.identifier.urihttp://hdl.handle.net/2152/3199en
dc.descriptiontexten
dc.description.abstractCell proliferation and differentiation are coordinated by synchronized patterns of gene expression. The regulation of these patterns is achieved, in part, through epigenetic mechanisms that affect the nature of DNA packaging into chromatin. Specifically, post-translational modifications to histone tails impact the structural dynamics of nucleosomes, thereby affecting DNA accessibility to transcriptional complexes. Accumulating evidence suggests that transcriptional regulators facilitate these alterations, resulting in altered local gene transcription. Thus, the structural interpretations of histone modifications are responsible for the establishment and maintenance of discrete programs of gene expression that ultimately correspond with distinct biological outcomes. Most histone lysine methyltransferases catalyze methyl transfer by way of the SET domain, a module encoded within many proteins that regulate diverse processes, including some critical for development and proper progression of the cell cycle. One such group of proteins, the SET and MYND domain (Smyd) family have been demonstrated to be direct regulators of tumorigenesis and essential developmental processes. Presented here is a functional characterization of two members of that family, Smyd2 and Smyd3. Smyd2 is identified as a member of the Smyd family and reported here to possess SET-dependent histone H3, lysine 36-specific methyltransferase activity. Smyd2 specifically associates with the Sin3A histone deacetylase complex, suggesting a link between two independent chromatin modification activities. Finally, over-expression of Smyd2 in fibroblasts is shown to significantly suppress their rate of growth. It is therefore proposed that Smyd2-mediated chromatin modifications regulate specific gene expression, thereby having important implications for normal and neoplastic cell proliferation. Aberrant expression of the histone H3-lysine 4-specific methyltransferase, Smyd3, has been implicated in colorectal, hepatocellular, and breast cell carcinogenesis. Here, Smyd3 is also shown to target histone H4, lysine 20 (H4K20). However, over-expression of Smyd3 in fibroblasts results in global reduction of trimethylation at H4K20 and this is accompanied by a striking increase in cell proliferation. As the methylation of H3K4 and H4K20 are normally associated with conflicting biological functions, I predict that these differential activities of Smyd3 are manifest under spatially and/or temporally distinct conditions, in the presence of different associating complexes, thereby resulting in effects that may be antagonistic of one another.en
dc.format.mediumelectronicen
dc.language.isoengen
dc.rightsCopyright is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works.en
dc.subject.lcshCell proliferationen
dc.subject.lcshCell differentiationen
dc.titleFunctional characterization of the split SET and MYND domain-containing methyltransferases, Smyd2 & Smyd3en
dc.description.departmentMicrobiologyen
dc.identifier.oclc173649799en
dc.type.genreThesisen
thesis.degree.departmentMicrobiologyen
thesis.degree.disciplineMicrobiologyen
thesis.degree.grantorThe University of Texas at Austinen
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen


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