Direct regulation of E-cadherin by targeted histone methylation of TALE-SET fusion protein in cancer cells

// Hyun-Soo Cho 1, * , Jeong Gu Kang 3, * , Jae-Hye Lee 1, 4, * , Jeong-Ju Lee 2 , Seong Kook Jeon 3 , Jeong-Heon Ko 3 , Dae-Soo Kim 2 , Kun-Hyang Park 2 , Yong-Sam Kim 3 , Nam-Soon Kim 1, 2, 4 1 Genomics Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-333, Republic of Korea 2 Human Derived Material Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-333, Republic of Korea 3 Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-333, Republic of Korea 4 Department of Functional Genomics, Korea University of Science and Technology, Daejeon, 305-333, Republic of Korea * These authors have contributed equally to this work Correspondence to: Nam-Soon Kim, e-mail: nskim37@kribb.re.kr Keywords: TALEN, histone methylation, migration, cancer Received: February 12, 2015      Accepted: June 09, 2015      Published: June 19, 2015 ABSTRACT TALE-nuclease chimeras (TALENs) can bind to and cleave specific genomic loci and, are used to engineer gene knockouts and additions. Recently, instead of using the FokI domain, epigenetically active domains, such as TET1 and LSD1, have been combined with TAL effector domains to regulate targeted gene expression via DNA and histone demethylation. However, studies of histone methylation in the TALE system have not been performed. Therefore, in this study, we established a novel targeted regulation system with a TAL effector domain and a histone methylation domain. To construct a TALE-methylation fusion protein, we combined a TAL effector domain containing an E-Box region to act as a Snail binding site and the SET domain of EHMT 2 to allow for histone methylation. The constructed TALE-SET module (TSET) repressed the expression of E-cadherin via by increasing H3K9 dimethylation. Moreover, the cells that overexpressed TSET showed increased cell migration and invasion. This is the first phenotype-based study of targeted histone methylation by the TALE module, and this new system can be applied in new cancer therapies to reduce side effects.