Architecture of epigenetic reprogramming following Twist1-mediated epithelial-mesenchymal transition

Gabriel G. Malouf, Joseph H. Taube, Yue Lu, Tapasree Roysarkar, Shoghag Panjarian, Marcos R.H. Estecio, Jaroslav Jelinek, Jumpei Yamazaki, Noel J.M. Raynal, Hai Long, Tomomitsu Tahara, Agata Tinnirello, Priyanka Ramachandran, Xiu Ying Zhang, Shoudan Liang, Sendurai A. Mani, Jean Pierre J. Issa

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Abstract

Background: Epithelial-mesenchymal transition (EMT) is known to impart metastasis and stemness characteristics in breast cancer. To characterize the epigenetic reprogramming following Twist1-induced EMT, we characterized the epigenetic and transcriptome landscapes using whole-genome transcriptome analysis by RNA-seq, DNA methylation by digital restriction enzyme analysis of methylation (DREAM) and histone modifications by CHIP-seq of H3K4me3 and H3K27me3 in immortalized human mammary epithelial cells relative to cells induced to undergo EMT by Twist1. Results: EMT is accompanied by focal hypermethylation and widespread global DNA hypomethylation, predominantly within transcriptionally repressed gene bodies. At the chromatin level, the number of gene promoters marked by H3K4me3 increases by more than one fifth; H3K27me3 undergoes dynamic genomic redistribution characterized by loss at half of gene promoters and overall reduction of peak size by almost half. This is paralleled by increased phosphorylation of EZH2 at serine 21. Among genes with highly altered mRNA expression, 23.1% switch between H3K4me3 and H3K27me3 marks, and those point to the master EMT targets and regulators CDH1, PDGFRa and ESRP1. Strikingly, Twist1 increases the number of bivalent genes by more than two fold. Inhibition of the H3K27 methyltransferases EZH2 and EZH1, which form part of the Polycomb repressive complex 2 (PRC2), blocks EMT and stemness properties. Conclusions: Our findings demonstrate that the EMT program requires epigenetic remodeling by the Polycomb and Trithorax complexes leading to increased cellular plasticity. This suggests that inhibiting epigenetic remodeling and thus decrease plasticity will prevent EMT, and the associated breast cancer metastasis.

Original languageEnglish
Article numberR144
JournalGenome Biology
Volume14
Issue number12
DOIs
Publication statusPublished - 01-01-2013

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Epithelial-Mesenchymal Transition
Epigenomics
epigenetics
gene
methylation
genes
metastasis
breast neoplasms
plasticity
cancer
promoter regions
Genes
DNA
restriction mapping
methyltransferases
DNA methylation
Polycomb Repressive Complex 2
transcriptomics
Histone Code
histones

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Cite this

Malouf, G. G., Taube, J. H., Lu, Y., Roysarkar, T., Panjarian, S., Estecio, M. R. H., ... Issa, J. P. J. (2013). Architecture of epigenetic reprogramming following Twist1-mediated epithelial-mesenchymal transition. Genome Biology, 14(12), [R144]. https://doi.org/10.1186/gb-2013-14-12-r144
Malouf, Gabriel G. ; Taube, Joseph H. ; Lu, Yue ; Roysarkar, Tapasree ; Panjarian, Shoghag ; Estecio, Marcos R.H. ; Jelinek, Jaroslav ; Yamazaki, Jumpei ; Raynal, Noel J.M. ; Long, Hai ; Tahara, Tomomitsu ; Tinnirello, Agata ; Ramachandran, Priyanka ; Zhang, Xiu Ying ; Liang, Shoudan ; Mani, Sendurai A. ; Issa, Jean Pierre J. / Architecture of epigenetic reprogramming following Twist1-mediated epithelial-mesenchymal transition. In: Genome Biology. 2013 ; Vol. 14, No. 12.
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abstract = "Background: Epithelial-mesenchymal transition (EMT) is known to impart metastasis and stemness characteristics in breast cancer. To characterize the epigenetic reprogramming following Twist1-induced EMT, we characterized the epigenetic and transcriptome landscapes using whole-genome transcriptome analysis by RNA-seq, DNA methylation by digital restriction enzyme analysis of methylation (DREAM) and histone modifications by CHIP-seq of H3K4me3 and H3K27me3 in immortalized human mammary epithelial cells relative to cells induced to undergo EMT by Twist1. Results: EMT is accompanied by focal hypermethylation and widespread global DNA hypomethylation, predominantly within transcriptionally repressed gene bodies. At the chromatin level, the number of gene promoters marked by H3K4me3 increases by more than one fifth; H3K27me3 undergoes dynamic genomic redistribution characterized by loss at half of gene promoters and overall reduction of peak size by almost half. This is paralleled by increased phosphorylation of EZH2 at serine 21. Among genes with highly altered mRNA expression, 23.1{\%} switch between H3K4me3 and H3K27me3 marks, and those point to the master EMT targets and regulators CDH1, PDGFRa and ESRP1. Strikingly, Twist1 increases the number of bivalent genes by more than two fold. Inhibition of the H3K27 methyltransferases EZH2 and EZH1, which form part of the Polycomb repressive complex 2 (PRC2), blocks EMT and stemness properties. Conclusions: Our findings demonstrate that the EMT program requires epigenetic remodeling by the Polycomb and Trithorax complexes leading to increased cellular plasticity. This suggests that inhibiting epigenetic remodeling and thus decrease plasticity will prevent EMT, and the associated breast cancer metastasis.",
author = "Malouf, {Gabriel G.} and Taube, {Joseph H.} and Yue Lu and Tapasree Roysarkar and Shoghag Panjarian and Estecio, {Marcos R.H.} and Jaroslav Jelinek and Jumpei Yamazaki and Raynal, {Noel J.M.} and Hai Long and Tomomitsu Tahara and Agata Tinnirello and Priyanka Ramachandran and Zhang, {Xiu Ying} and Shoudan Liang and Mani, {Sendurai A.} and Issa, {Jean Pierre J.}",
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Malouf, GG, Taube, JH, Lu, Y, Roysarkar, T, Panjarian, S, Estecio, MRH, Jelinek, J, Yamazaki, J, Raynal, NJM, Long, H, Tahara, T, Tinnirello, A, Ramachandran, P, Zhang, XY, Liang, S, Mani, SA & Issa, JPJ 2013, 'Architecture of epigenetic reprogramming following Twist1-mediated epithelial-mesenchymal transition', Genome Biology, vol. 14, no. 12, R144. https://doi.org/10.1186/gb-2013-14-12-r144

Architecture of epigenetic reprogramming following Twist1-mediated epithelial-mesenchymal transition. / Malouf, Gabriel G.; Taube, Joseph H.; Lu, Yue; Roysarkar, Tapasree; Panjarian, Shoghag; Estecio, Marcos R.H.; Jelinek, Jaroslav; Yamazaki, Jumpei; Raynal, Noel J.M.; Long, Hai; Tahara, Tomomitsu; Tinnirello, Agata; Ramachandran, Priyanka; Zhang, Xiu Ying; Liang, Shoudan; Mani, Sendurai A.; Issa, Jean Pierre J.

In: Genome Biology, Vol. 14, No. 12, R144, 01.01.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Architecture of epigenetic reprogramming following Twist1-mediated epithelial-mesenchymal transition

AU - Malouf, Gabriel G.

AU - Taube, Joseph H.

AU - Lu, Yue

AU - Roysarkar, Tapasree

AU - Panjarian, Shoghag

AU - Estecio, Marcos R.H.

AU - Jelinek, Jaroslav

AU - Yamazaki, Jumpei

AU - Raynal, Noel J.M.

AU - Long, Hai

AU - Tahara, Tomomitsu

AU - Tinnirello, Agata

AU - Ramachandran, Priyanka

AU - Zhang, Xiu Ying

AU - Liang, Shoudan

AU - Mani, Sendurai A.

AU - Issa, Jean Pierre J.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Background: Epithelial-mesenchymal transition (EMT) is known to impart metastasis and stemness characteristics in breast cancer. To characterize the epigenetic reprogramming following Twist1-induced EMT, we characterized the epigenetic and transcriptome landscapes using whole-genome transcriptome analysis by RNA-seq, DNA methylation by digital restriction enzyme analysis of methylation (DREAM) and histone modifications by CHIP-seq of H3K4me3 and H3K27me3 in immortalized human mammary epithelial cells relative to cells induced to undergo EMT by Twist1. Results: EMT is accompanied by focal hypermethylation and widespread global DNA hypomethylation, predominantly within transcriptionally repressed gene bodies. At the chromatin level, the number of gene promoters marked by H3K4me3 increases by more than one fifth; H3K27me3 undergoes dynamic genomic redistribution characterized by loss at half of gene promoters and overall reduction of peak size by almost half. This is paralleled by increased phosphorylation of EZH2 at serine 21. Among genes with highly altered mRNA expression, 23.1% switch between H3K4me3 and H3K27me3 marks, and those point to the master EMT targets and regulators CDH1, PDGFRa and ESRP1. Strikingly, Twist1 increases the number of bivalent genes by more than two fold. Inhibition of the H3K27 methyltransferases EZH2 and EZH1, which form part of the Polycomb repressive complex 2 (PRC2), blocks EMT and stemness properties. Conclusions: Our findings demonstrate that the EMT program requires epigenetic remodeling by the Polycomb and Trithorax complexes leading to increased cellular plasticity. This suggests that inhibiting epigenetic remodeling and thus decrease plasticity will prevent EMT, and the associated breast cancer metastasis.

AB - Background: Epithelial-mesenchymal transition (EMT) is known to impart metastasis and stemness characteristics in breast cancer. To characterize the epigenetic reprogramming following Twist1-induced EMT, we characterized the epigenetic and transcriptome landscapes using whole-genome transcriptome analysis by RNA-seq, DNA methylation by digital restriction enzyme analysis of methylation (DREAM) and histone modifications by CHIP-seq of H3K4me3 and H3K27me3 in immortalized human mammary epithelial cells relative to cells induced to undergo EMT by Twist1. Results: EMT is accompanied by focal hypermethylation and widespread global DNA hypomethylation, predominantly within transcriptionally repressed gene bodies. At the chromatin level, the number of gene promoters marked by H3K4me3 increases by more than one fifth; H3K27me3 undergoes dynamic genomic redistribution characterized by loss at half of gene promoters and overall reduction of peak size by almost half. This is paralleled by increased phosphorylation of EZH2 at serine 21. Among genes with highly altered mRNA expression, 23.1% switch between H3K4me3 and H3K27me3 marks, and those point to the master EMT targets and regulators CDH1, PDGFRa and ESRP1. Strikingly, Twist1 increases the number of bivalent genes by more than two fold. Inhibition of the H3K27 methyltransferases EZH2 and EZH1, which form part of the Polycomb repressive complex 2 (PRC2), blocks EMT and stemness properties. Conclusions: Our findings demonstrate that the EMT program requires epigenetic remodeling by the Polycomb and Trithorax complexes leading to increased cellular plasticity. This suggests that inhibiting epigenetic remodeling and thus decrease plasticity will prevent EMT, and the associated breast cancer metastasis.

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U2 - 10.1186/gb-2013-14-12-r144

DO - 10.1186/gb-2013-14-12-r144

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