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| Subject Categories: Chromatin & Transcription |
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| The EMBO Journal
(2004) 23, 138–149, doi:10.1038/sj.emboj.7600013 Published online 11 December 2003 |
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| Silencing of transgene transcription precedes methylation of promoter DNA and histone H3 lysine 9 |
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| Vesco Mutskov and Gary Felsenfeld |
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Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, MD, USA To whom correspondence should be addressed Gary Felsenfeld, NIH-NIDDK LMB, Building 5, Room 212, 5 Center Drive, MSC 0540, Bethesda, MD 20892-0540, USA. Tel.: +1 301 496 4173; Fax: +1 301 496 0201; E-mail: gary.felsendfeld@nih.gov Received 22 May 2003; Accepted 15 October 2003; Published online 11 December 2003. |
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| Abstract |
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| Transgenes stably integrated into cells or animals in many cases are silenced rapidly, probably under the influence of surrounding endogenous condensed chromatin. This gene silencing correlates with repressed chromatin structure marked by histone hypoacetylation, loss of methylation at H3 lysine 4, increase of histone H3 lysine 9 methylation as well as CpG DNA methylation at the promoter. However, the order and the timing of these modifications and their impact on transcription inactivation are less well understood. To determine the temporal order of these events, we examined a model system consisting of a transgenic cassette stably integrated in chicken erythroid cells. We found that histone H3 and H4 hypoacetylation and loss of methylation at H3 lysine 4 all occurred during the same window of time as transgene inactivation in both multicopy and low-copy-number lines. These results indicate that these histone modifications were the primary events in gene silencing. We show that the kinetics of silencing exclude histone H3 K9 and promoter DNA methylation as the primary causative events in our transgene system. |
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| Keywords: chromatin, DNA methylation, histone acetylation, histone methylation, transgene silencing |
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