Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition

Abstract

Epithelial-to-mesenchymal transition (EMT) is an extreme example of cell plasticity that is important for normal development, injury repair and malignant progression. Widespread epigenetic reprogramming occurs during stem cell differentiation and malignant transformation, but EMT-related epigenetic reprogramming is poorly understood. Here we investigated epigenetic modifications during EMT mediated by transforming growth factor beta. Although DNA methylation was unchanged during EMT, we found a global reduction in the heterochromatin mark H3 Lys9 dimethylation (H3K9Me2), an increase in the euchromatin mark H3 Lys4 trimethylation (H3K4Me3) and an increase in the transcriptional mark H3 Lys36 trimethylation (H3K36Me3). These changes depended largely on lysine-specific demethylase-1 (Lsd1), and loss of Lsd1 function had marked effects on EMT-driven cell migration and chemoresistance. Genome-scale mapping showed that chromatin changes were mainly specific to large organized heterochromatin K9 modifications (LOCKs), which suggests that EMT is characterized by reprogramming of specific chromatin domains across the genome.

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Figure 1: Global changes in bulk chromatin modifications during EMT.
Figure 2: Lsd1 regulates bulk changes in chromatin modifications during EMT.
Figure 3: Lsd1 regulates certain EMT phenotypes.
Figure 4: ChIP-chip analysis of EMT reveals alterations of chromatin in LOCK domains.

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Acknowledgements

This work was supported by US National Institutes of Health grant 5R37CA054358 to A.P.F. We thank A. Tackett for assistance with mass spectrometry experiments and data analysis; C. McCall for advice on large-scale immunoprecipitation experiments; the microscopy facility at Johns Hopkins University for electron microscopy; and K. Reddy and S. Taverna for advice.

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O.G.M. and A.P.F. conceived this work, designed the experiments and wrote the manuscript. H.W. performed the statistical analyses. W.T. performed the immunofluorescence. A.D. performed the CHARM.

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Correspondence to Andrew P Feinberg.

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The authors declare no competing financial interests.

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Supplementary Figures 1–9 and Supplementary Tables 1–5 (PDF 2802 kb)

Supplementary Data 1

Locations of K9Me2 LOCKs identified in AML12 cells (XLSX 183 kb)

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McDonald, O., Wu, H., Timp, W. et al. Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nat Struct Mol Biol 18, 867–874 (2011). https://doi.org/10.1038/nsmb.2084

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