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Nucleic Acids Research Advance Access published online on April 29, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn066
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Identification of transcriptional regulatory cascades in retinoic acid-induced growth arrest of HepG2 cells

Misato Nakanishi1,2, Yasuhiro Tomaru1,2, Hisashi Miura1,2, Yoshihide Hayashizaki1,2,3 and Masanori Suzuki1,2,*

1Laboratory of Genome Exploration Research Group, RIKEN Genomic Sciences Center (GSC), RIKEN Yokohama Institute 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, 2Division of Genomics, Supramolecular Biology, International Graduate School of Arts and Sciences, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 and 3Genome Science Laboratory, Discovery and Research Institute, RIKEN Wako Main Campus, 2-1 Hirosawa, Wako, 351-0198, Japan

*To whom correspondence should be addressed. Tel: +81 045 508 7241; Fax: +81 045 508 7370; Email: msuzuki{at}gsc.riken.jp; msuzuki{at}tsurumi.yokohama-cu.ac.jp

Received November 6, 2007. Revised January 30, 2008. Accepted February 3, 2008.

All-trans retinoic acid (ATRA) is a potent inducer of cell differentiation and growth arrest. Here, we investigated ATRA-induced regulatory cascades associated with growth arrest of the human hepatoma cell line HepG2. ATRA induced >2-fold changes in the expression of 402 genes including 55 linked to cell-cycle regulation, cell growth or apoptosis during 48 h treatment. Computational search predicted that 250 transcriptional regulatory factors (TRFs) could recognize the proximal upstream regions of any of the 55 genes. Expression of 61 TRF genes was significantly changed during ATRA incubation, providing many potential regulatory edges. We focused on six TRFs that could regulate many of the 55 genes and found a total of 160 potential edges in which the expression of each of the genes was changed later than the expression change of the corresponding regulator. RNAi knockdown of the selected TRFs caused perturbation of the respective potential targets. The genes showed an opposite regulation pattern by ATRA and specific siRNA treatments were selected as strong candidates for direct TRF targets. Finally, 36 transcriptional regulatory edges were validated by chromatin immunoprecipitation. These analyses enabled us to depict a part of the transcriptional regulatory cascades closely linked to ATRA-induced cell growth arrest.


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