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First published online December 21, 2005
doi: 10.1242/10.1242/jcs.02727
Research Article |
1 Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
2 MIT Center for Cancer Research, Building E17-51, 40 Ames Street, Cambridge, MA 02139, USA
3 Mathematical & Statistical Computing Laboratory, Division of Computational Bioscience, Center for Information Technology, 12 South Drive, Bethesda, MD 20892, USA
4 Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Building 41, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA
* Authors for correspondence (e-mail: ruth.williams{at}csc.mrc.ac.uk; amanda.fisher{at}csc.mrc.ac.uk)
Accepted 4 October 2005
Determining how genes are epigenetically regulated to ensure their correct spatial and temporal expression during development is key to our understanding of cell lineage commitment. Here we examined epigenetic changes at an important proneural regulator gene Mash1 (Ascl1), as embryonic stem (ES) cells commit to the neural lineage. In ES cells where the Mash1 gene is transcriptionally repressed, the locus replicated late in S phase and was preferentially positioned at the nuclear periphery with other late-replicating genes (Neurod, Sprr2a). This peripheral location was coupled with low levels of histone H3K9 acetylation at the Mash1 promoter and enhanced H3K27 methylation but surprisingly location was not affected by removal of the Ezh2/Eed HMTase complex or several other chromatin-silencing candidates (G9a, SuV39h-1, Dnmt-1, Dnmt-3a and Dnmt-3b). Upon neural induction however, Mash1 transcription was upregulated (>100-fold), switched its time of replication from late to early in S phase and relocated towards the interior of the nucleus. This spatial repositioning was selective for neural commitment because Mash1 was peripheral in ES-derived mesoderm and other non-neural cell types. A bidirectional analysis of replication timing across a 2 Mb region flanking the Mash1 locus showed that chromatin changes were focused at Mash1. These results suggest that Mash1 is regulated by changes in chromatin structure and location and implicate the nuclear periphery as an important environment for maintaining the undifferentiated state of ES cells.
Key words: Chromatin, Transcription, Replication timing, Nuclear organization, Neurogenesis, Epigenetics, Proneural
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