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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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.
Supplementary Methods, Supplementary Tables 1–8 and Supplementary Figures 1–11 (PDF 478 kb)
H3K9Me2 LOCKs in human placenta (XLS 24 kb)
H3K9Me2 LOCKs in mouse (XLS 1258 kb)
H3K9Me2 LOCKs in WT and G9a−/− day 18-differentiated ES cells (XLS 28 kb)
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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