Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597647
Title: Interaction of REST with ATAD2 promotes neuronal gene expression
Author: Choudhary, P.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2009
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Abstract:
Repressor Element 1 (RE1) Silencing Transcription factor (REST, also known as Neuron Restrictive Silencer Factor, NRSF) is a key regulator of gene expression in development. REST has been characterized as a repressor that silences neuronal genes in non-neuronal cells and neuronal precursors through interactions with co-repressor proteins, such as CoREST. In this thesis, I show for the first time that REST interacts with the AAA ATPase and Bromodomain containing protein, ATAD2, leading to activation of target genes. ATAD2 and REST bind in a mutually dependent manner to chromatin during a discrete window of the cell cycle. This occurs before REST is degraded and previously REST-repressed genes become transiently activated. Overexpression of ATAD2 leads to a loss of CoREST occupancy at target sites, suggesting that ATAD2 counteracts repression by displacing CoREST. As a result, the observed activation of target genes may be a result of their de-repression from the REST repressor complex. I propose that this cell cycle-coupled burst of transcriptional activity is required for differentiation, as it primes repressed genes for activation. Consistent with this hypothesis, ATAD2 promotes REST-mediated gene expression during differentiation of neuronal precursor cells. Taken together, my data reveal that gene control by REST may involve a successive interplay of repressive and activating functions. This highlights an unexpected layer of regulatory mechanism in REST function.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.597647  DOI: Not available
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