Oncotarget

Research Papers:

Epigenetic landscape change analysis during human EMT sheds light on a key EMT mediator TRIM29

Sung Kyung Choi, Kurinji Pandiyan, Jung Woo Eun, Xiaojing Yang, Seong Hwi Hong, Suk Woo Nam, Peter A. Jones, Gangning Liang and Jueng Soo You _

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Oncotarget. 2017; 8:98322-98335. https://doi.org/10.18632/oncotarget.21681

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Abstract

Sung Kyung Choi1,*, Kurinji Pandiyan2,3,*, Jung Woo Eun4, Xiaojing Yang2, Seong Hwi Hong1, Suk Woo Nam4, Peter A. Jones5, Gangning Liang2 and Jueng Soo You1,6

1Department of Biochemistry, School of Medicine, Konkuk University, Seoul, Korea

2Departments of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

3Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA

4Department of Pathology, College of Medicine, The Catholic University, Seoul, Korea

5Van Andel Research Institute, Grand Rapids, MI, USA

6Research Institute of Medical Science, KonKuk University School of Medicine, Seoul, Korea

*These authors contributed equally to this work

Correspondence to:

Jueng Soo You, email: [email protected]

Keywords: epigenetic landscape, EMT, DNA methylation, chromatin accessibility, TRIM29

Received: August 01, 2017     Accepted: September 22, 2017     Published: October 09, 2017

ABSTRACT

Epithelial to mesenchymal transition (EMT) is a key trans-differentiation process, which plays a critical role in physiology and pathology. Although gene expression changes in EMT have been scrutinized, study of epigenome is in its infancy. To understand epigenetic changes during TWIST-driven EMT, we used the AcceSssIble assay to study DNA methylation and chromatin accessibility in human mammary epithelial cells (HMECs). The DNA methylation changes were found to have functional significance in EMT – i.e. methylated genes were enriched for E-box motifs that can be recognized by TWIST, at the promoters suggesting a potential targeting phenomenon, whereas the demethylated regions were enriched for pro-metastatic genes, supporting the role of EMT in metastasis. TWIST-induced EMT triggers alterations in chromatin accessibility both independent of and dependent on DNA methylation changes, primarily resulting in closed chromatin conformation. By overlapping the genes, whose chromatin structure is changed during early EMT and a known “core EMT signature”, we identified 18 driver candidate genes during EMT, 14 upregulated and 4 downregulated genes with corresponding chromatin structure changes. Among 18 genes, we focused on TRIM29 as a novel marker of EMT. Although loss of TRIM29 is insufficient to suppress CDH, it is enough to induce CDH2 and VIM. Gene functional annotation analysis shows the involvement of TRIM29 in epidermal development, cell differentiation and cell migration. Taken together, our results provide a robust snapshot of chromatin state during human EMT and identify TRIM29 as a core mediator of EMT.


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