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Histone modification, gene regulation and epigenetic memory in embryonic stem cells

Boudadi, Elsa (2011)
Ph.D. thesis, University of Birmingham.

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Histone modifications are thought to act as a layer of epigenetic information, because of their strong association with gene expression, and their potential role in transcriptional memory. However, although specific histone modifications correlate with transcriptional status, whether they play a causative role or act in the long term
inheritance of gene expression patterns is unclear.

In order to explore this, the histone deacetylase inhibitor valproic acid (VPA) was used to induce hyperacetylation of histones in embryonic stem cells. Surprisingly, although global levels of acetyl marks were highly increased by VPA treatment (up to 16-fold), only 10% of genes showed transcriptional changes. Interestingly, these global changes in histone modification were not reflected in the changes at individual genes where increases in acetylation were rarely greater than 2-fold. Furthermore, changes in acetylation levels did not correlate with transcriptional effects. Wash-out experiments showed that transient VPA treatment could not induce long term effects on transcription, even during ES cell differentiation when histone modifications play a crucial role. Finally, the role of polycomb silencing in the response to VPA treatment was assessed using an ES cell line in which the polycomb components Eed and Ring1b had been knocked out. Target genes showed small up-regulation in knockout cells but VPA did not further induce transcription.

It was concluded that histone acetylation plays an important role in transcription but additional signals are required for transcriptional induction and cellular memory. My results suggest the existence of protective mechanisms against hyperacetylation and highlight the complexity of epigenetic regulation, potentially involving many layers of control.

Type of Work:Ph.D. thesis.
Supervisor(s):Turner, Bryan M.
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Institute of Biomedical Research
Subjects:RB Pathology
Institution:University of Birmingham
ID Code:3160
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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