Date of Award
Dissertation - MUSC Only
Doctor of Philosophy (PhD)
Biochemistry and Molecular Biology
College of Graduate Studies
David T. Long
Modification of histones provides a dynamic mechanism to regulate chromatin structure and access to DNA. Histone acetylation and methylation, in particular, play prominent roles in controlling the interaction between DNA, histones, and other chromatin- associated proteins. Utilizing Xenopus laevis egg extracts, we have investigated how changes in both histone methylation and acetylation control different processes such as transcription of chromatinized DNA substrates and DNA repair. Defects in histone acetylation interfere with normal gene expression and underlie a wide range of human diseases. We investigate how changes in histone acetylation influence transcription of a defined gene construct. We show that inhibition of histone deacetylase 1 and 2 (HDAC1/2) specifically counteracts transcription suppression by preventing chromatin compaction and deacetylation of histone residues H4K5, H4K8, and H4K12. Acetylation of these sites supports binding of the chromatin reader and transcription regulator BRD4. We also identify HDAC1 as the primary driver of transcription suppression and show that this activity is mediated through the Sin3 histone deacetylase complex. These findings highlight functional differences between HDAC1 and HDAC2, which are often considered to be functionally redundant, and provide additional molecular context for their activity. H4K20 methylation signaling, specifically H4K20me0, has been associated with post replicated chromatin and certain DNA repair proteins. We show that introduction of exogenous methyltransferase SET8 upregulates H4K20me1 and abrogates the recruitment of certain repair proteins involved in the repair of inter-strand crosslinks.
Quaas, Colleen Elizabeth, "Regulation of Chromatin Modifiers During Transcription and Damage Signaling in Xenopus Egg Extract" (2022). MUSC Theses and Dissertations. 679.
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Available for download on Friday, March 07, 2025