ChIP-on-chip analysis of thyroid hormone-regulated genes and their physiological significance

// I-Hsiao Chung 1 * , Hsuan Liu 1, 2, 6 * , Yang-Hsiang Lin 1 , Hsiang-Cheng Chi 1 , Ya-Hui Huang 3 , Chang-Ching Yang 2, 4 , Chau-Ting Yeh 3 , Bertrand Chin-Ming Tan 2, 4, 5 , Kwang-Huei Lin 1, 3 1 Department of Biochemistry, College of Medicine, Chang Gung University, Taoyuan, Taiwan 2 Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan 3 Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan 4 Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan 5 Department of Neurosurgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan 6 Colorectal Section, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan * These authors have contributed equally to this work Correspondence to: Bertrand Chin-Ming Tan, e-mail: btan@mail.cgu.edu.tw Kwang-Huei Lin, e-mail: khlin@mail.cgu.edu.tw Keywords: thyroid hormone receptor, ChIP-on-chip, cell growth, ELF2 Received: October 30, 2015      Accepted: February 23, 2016      Published: March 8, 2016 ABSTRACT Triiodothyronine (T 3 ) and its receptor (TR) modulate several physiological processes, including cell development, proliferation, differentiation and metabolism. The regulatory mechanism of T 3 /TR involves binding to the thyroid hormone response element (TRE) within the target gene promoter. However, the number of target genes directly regulated by TRα1 and the specific pathways of TR-regulated target genes remain largely unknown. Here, we expressed TRα1 in a HepG2 cell line and used chromatin immunoprecipitation coupled with microarray to determine the genes that are directly regulated by TRα1 and also involved in cell metabolism and proliferation. Our analysis identified E74-like factor 2 (ELF2), a transcription factor associated with tumor growth, as a direct target downregulated by T 3 /TR. Overexpression of ELF2 enhanced tumor cell proliferation, and conversely, its knockdown suppressed tumor growth. Additionally, ELF2 restored the proliferative ability of hepatoma cells inhibited by T 3 /TR. Our findings collectively support a potential role of T 3 /TR in tumor growth inhibition through regulation of ELF2.