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Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells

Abstract

Higher eukaryotes must adapt a totipotent genome to specialized cell types with stable but limited functions. One potential mechanism for lineage restriction is changes in chromatin, and differentiation-related chromatin changes have been observed for individual genes1,2. We have taken a genome-wide view of histone H3 lysine 9 dimethylation (H3K9Me2) and find that differentiated tissues show surprisingly large K9-modified regions (up to 4.9 Mb). These regions are highly conserved between human and mouse and are differentiation specific, covering only 4% of the genome in undifferentiated mouse embryonic stem (ES) cells, compared to 31% in differentiated ES cells, 46% in liver and 10% in brain. These modifications require histone methyltransferase G9a and are inversely related to expression of genes within the regions. We term these regions large organized chromatin K9 modifications (LOCKs). LOCKs are substantially lost in cancer cell lines, and they may provide a cell type–heritable mechanism for phenotypic plasticity in development and disease.

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Figure 1: LOCK-like clustering of histone H3 lysine-9 dimethylation (H3K9Me2) in human placenta.
Figure 2: H3K9Me2 LOCKs are conserved between human and mouse.
Figure 3: H3K9Me2 LOCKs arise during differentiation.
Figure 4: Tissue-specific H3K9Me2 LOCKs are associated with differential gene expression in liver and brain.
Figure 5: Model of epigenetic memory of cell type–specific higher-order chromatin structure mediated by H3K9Me2 LOCKs.

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Acknowledgements

We thank S. Taverna, K. Reddy, R. Ohlsson and C. Sapienza for helpful discussions, and S. Taverna and W. Timp for assistance with illustration. This work was supported by US National Institutes of Health grant P50HG003233 to A.P.F.

Author information

Authors and Affiliations

Authors

Contributions

B.W. and A.P.F. conceived the project. B.W. performed the experiments. H.W. analyzed the data with the guidance of R.A.I. Y.S. provided the mouse G9a knockout and control ES cell lines. A.P.F. supervised the experiments and wrote the paper with B.W.

Corresponding author

Correspondence to Andrew P Feinberg.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Tables 1–8 and Supplementary Figures 1–11 (PDF 478 kb)

Supplementary Data 1

H3K9Me2 LOCKs in human placenta (XLS 24 kb)

Supplementary Data 2

H3K9Me2 LOCKs in mouse (XLS 1258 kb)

Supplementary Data3

H3K9Me2 LOCKs in WT and G9a−/− day 18-differentiated ES cells (XLS 28 kb)

Supplementary Data 4

Individual H3K9Me2 and H3K9Me3 marks in WT and G9a−/− day 18-differentiated ES cells (XLS 75 kb)

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Wen, B., Wu, H., Shinkai, Y. et al. Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nat Genet 41, 246–250 (2009). https://doi.org/10.1038/ng.297

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