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

被引:69
作者
Malouf, Gabriel G. [1 ,2 ]
Taube, Joseph H. [3 ,5 ]
Lu, Yue [1 ]
Roysarkar, Tapasree [3 ,5 ]
Panjarian, Shoghag [6 ]
Estecio, Marcos R. H. [1 ]
Jelinek, Jaroslav [1 ]
Yamazaki, Jumpei [1 ]
Raynal, Noel J-M [1 ]
Long, Hai [1 ]
Tahara, Tomomitsu [1 ]
Tinnirello, Agata [3 ]
Ramachandran, Priyanka [3 ]
Zhang, Xiu-Ying [4 ]
Liang, Shoudan [4 ]
Mani, Sendurai A. [3 ,5 ]
Issa, Jean-Pierre J. [1 ,6 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA
[2] Inst Univ Cancorol, Fac Med Pierre & Marie Curie, Grp Hosp Pitie Salpetriere, Dept Med Oncol,AP HP, Paris, France
[3] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA
[4] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat, Houston, TX 77030 USA
[5] Univ Texas MD Anderson Canc Ctr, Metastasis Res Ctr, Houston, TX 77030 USA
[6] Temple Univ, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19122 USA
关键词
BREAST-CANCER; DNA METHYLATION; GENE-EXPRESSION; E-CADHERIN; CELLS; EZH2; METASTASIS; DOMAINS; IDENTIFICATION; REGULATOR;
D O I
10.1186/gb-2013-14-12-r144
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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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页数:17
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