OCT4 establishes and maintains nucleosome-depleted regions that provide additional layers of epigenetic regulation of its target genes
- 15 August 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (35), 14497-14502
- https://doi.org/10.1073/pnas.1111309108
Abstract
Recent epigenome-wide mapping studies describe nucleosome-depleted regions (NDRs) at transcription start sites and enhancers. However, these static maps do not address causality or the roles of NDRs in gene control, and their relationship to transcription factors and DNA methylation is not well understood. Using a high-resolution single-molecule mapping approach to simultaneously investigate endogenous DNA methylation and nucleosome occupancies on individual DNA molecules, we show that the unmethylated OCT4 distal enhancer has an NDR, whereas NANOG has a clear NDR at its proximal promoter. These NDRs are maintained by binding of OCT4 and are required for OCT4 and NANOG expression. Differentiation causes a rapid loss of both NDRs accompanied by nucleosome occupancy, which precedes de novo DNA methylation. NDRs can be restored by forced expression of OCT4 in somatic cells but only when there is no cytosine methylation. These data show the central role of the NDRs, established by OCT4, in ensuring the autoregulatory loop of pluripotency and, furthermore, that de novo methylation follows the loss of NDRs and stabilizes the suppressed state.Keywords
This publication has 47 references indexed in Scilit:
- Nucleosome positioning and gene regulation: advances through genomicsNature Reviews Genetics, 2009
- Epigenetic reprogramming and induced pluripotencyDevelopment, 2009
- Transcriptional and epigenetic regulations of embryonic stem cellsMutation Research, 2008
- De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genesNature Structural & Molecular Biology, 2008
- Genome-scale DNA methylation maps of pluripotent and differentiated cellsNature, 2008
- Dynamic Regulation of Nucleosome Positioning in the Human GenomeCell, 2008
- DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNANature, 2007
- Stability and flexibility of epigenetic gene regulation in mammalian developmentNature, 2007
- Nucleosomes inhibit the initiation of transcription but allow chain elongation with the displacement of histonesCell, 1987
- Methylation of the Hprt gene on the inactive X occurs after chromosome inactivationCell, 1987