Chandler, Simon P.; Kansagra, Pushpa and Hirst, Mark C.
(2003).
![[img]](http://oro.open.ac.uk/style/images/fileicons/application_pdf.png)
|
PDF (Not Set)
- Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Download (441kB) |
| DOI (Digital Object Identifier) Link: | https://doi.org/10.1186/1471-2199-4-3 |
|---|---|
| Google Scholar: | Look up in Google Scholar |
Abstract
Background
Expansion of an unstable (CGG)n repeat to over 200 triplets within the promoter region of the human FMR1 gene leads to extensive local methylation and transcription silencing, resulting in the loss of FMRP protein and the development of the clinical features of fragile X syndrome. The causative link between (CGG)n expansion, methylation and gene silencing is unknown, although gene silencing is associated with extensive changes to local chromatin architecture.
Results
In order to determine the direct effects of increased repeat length on gene transcription in a chromatin context, we have examined the influence of FMR1 (CGG)n repeats upon transcription from the HSV thymidine kinase promoter in the Xenopus laevis oocyte. We observe a reduction in mRNA production directly associated with increasing repeat length, with a 90% reduction in mRNA production from arrays over 100 repeats in length. Using a kinetic approach, we show that this transcriptional repression is concomitant with chromatin maturation and, using in vitro transcription, we show that chromatin formation is a fundamental part of the repressive pathway mediated by (CGG)n repeats. Using Trichostatin A, a histone deacetylase inhibitor, we show reactivation of the silenced promoter.
Conclusions
Thus, isolated fragile X associated (CGG)n repeat arrays can exert a modifying and transcriptionally repressive influence over adjacent promoters and this repressive phenomenon is, in part, mediated by histone deacetylation.
| Item Type: | Journal Item |
|---|---|
| ISSN: | 1471-2199 |
| Keywords: | gene silencing; gene transcription |
| Academic Unit/School: | Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences Faculty of Science, Technology, Engineering and Mathematics (STEM) |
| Interdisciplinary Research Centre: | Biomedical Research Network (BRN) |
| Item ID: | 43 |
| Depositing User: | Users 12 not found. |
| Date Deposited: | 09 May 2006 |
| Last Modified: | 16 Aug 2017 19:33 |
| URI: | http://oro.open.ac.uk/id/eprint/43 |
| Share this page: |     |
Altmetrics |
Download history for this item
These details should be considered as only a guide to the number of downloads performed manually. Algorithmic methods have been applied in an attempt to remove automated downloads from the displayed statistics but no guarantee can be made as to the accuracy of the figures.
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)