Histone acetylation plays an important role in regulating chromatin structure and thus gene expression. Analysis of histone deacetylase (HDAC) activity in S. cerevisiae revealed the presence of two deacetylase complexes, one containing Hda1 as its catalytic subunit, and the other possessing Rpd3. The three previously identified human HDAC proteins, HDAC1-3, were found to be homologs of Rpd3. This observation suggested that mammalian cells might contain an uncharacterized class of biochemically distinct Hda1-like proteins. The goal of my project has been to identify and characterize mammalian HDAC proteins which are similar to Hda1. I first identified the human histone deacetylase HDAC4, which contains a carboxy-terminal region significantly similar to the catalytic domain of yeast Hda1. When tethered to a promoter, HDAC4 functions as a transcription corepressor. Furthermore, HDAC4 interacts with the transcription factors MEF2 and RFXAf\lK and represses transcription of their target genes, supporting the notion that HDAC4 is a transcription corepressor in vivo. Surprisingly, HDAC4 is localized mainly in the cytoplasmic region and shuttles between the nucleus and the cytoplasm. Nucleocytoplasmic shuttling of HDAC4 is controlled by multiple mechanisms. HDAC4 possesses a nuclear localization signal (NLS) and a nuclear export signal (NES) for its dynamic nucleocytoplasmic trafficking. Binding of 14-3-3 proteins exposes the NES of HDAC4, which then results in its nuclear export. From this work, I have identified HDAC4 and shown that it functions as a transcription corepressor whose activity is regulated by nucleocytoplasmic shuttling.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.19445 |
| Date | January 2003 |
| Creators | Wang, Audrey Hongjun |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002010397, Theses scanned by McGill Library. |
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