Neural induction promotes large-scale chromatin reorganisation of theMash1locus
Open Access
- 1 January 2006
- journal article
- Published by The Company of Biologists in Journal of Cell Science
- Vol. 119 (1), 132-140
- https://doi.org/10.1242/jcs.02727
Abstract
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.Keywords
This publication has 59 references indexed in Scilit:
- BMP Induction of Id Proteins Suppresses Differentiation and Sustains Embryonic Stem Cell Self-Renewal in Collaboration with STAT3Cell, 2003
- The eukaryotic genome: a system regulated at different hierarchical levelsJournal of Cell Science, 2003
- Spatial proximity of translocation-prone gene loci in human lymphomasNature Genetics, 2003
- Genome-wide DNA replication profile for Drosophila melanogaster: a link between transcription and replication timingNature Genetics, 2002
- Proneural genes and the specification of neural cell typesNature Reviews Neuroscience, 2002
- Subnuclear Compartmentalization of Immunoglobulin Loci During Lymphocyte DevelopmentScience, 2002
- Subchromosomal Positioning of the Epidermal Differentiation Complex (EDC) in Keratinocyte and Lymphoblast Interphase NucleiExperimental Cell Research, 2002
- The replication timing program of the Chinese hamster β-globin locus is established coincident with its repositioning near peripheral heterochromatin in early G1 phaseThe Journal of cell biology, 2001
- Perturbation of Nuclear Architecture by Long-Distance Chromosome InteractionsCell, 1996
- The carboxy termini of Sir4 and Rap1 affect Sir3 localization: evidence for a multicomponent complex required for yeast telomeric silencing.The Journal of cell biology, 1995