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Cross-enhancement of ANGPTL4 transcription by HIF1 alpha and PPAR beta/delta is the result of the conformational proximity of two response elements

Tsuyoshi Inoue12, Takahide Kohro3, Toshiya Tanaka2, Yasuharu Kanki2, Guoliang Li4, Huay-Mei Poh5, Imari Mimura12, Mika Kobayashi2, Akashi Taguchi2, Takashi Maejima6, Jun-ichi Suehiro2, Akira Sugiyama2, Kiyomi Kaneki2, Hirofumi Aruga7, Shoulian Dong7, Junko F Stevens7, Shogo Yamamoto2, Shuichi Tsutsumi2, Toshiro Fujita2, Xiaoan Ruan5, Hiroyuki Aburatani2, Masaomi Nangaku1, Yijun Ruan4, Tatsuhiko Kodama2 and Youichiro Wada28*

Author Affiliations

1 Division of Nephrology and Endocrinology, School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

2 Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan

3 Department of Translational Research for Healthcare and Clinical Science, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

4 Jackson Laboratory for Genomic Medicine, 400 Farmington Ave, Farmington, CT 06032, USA

5 Genome Institute of Singapore, 60 Biopolis Street, #02-01, Genome 138672, Singapore

6 Tokyo New Drug Research Laboratories, Kowa Company Ltd, 2-17-43, Noguchicho, Higashimurayamashi, Tokyo 189-0022, Japan

7 Thermo Fisher Scientific, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA

8 Radioisotope Center, The University of Tokyo, 2-11-16, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan

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Genome Biology 2014, 15:R63  doi:10.1186/gb-2014-15-4-r63

Published: 10 April 2014



Synergistic transcriptional activation by different stimuli has been reported along with a diverse array of mechanisms, but the full scope of these mechanisms has yet to be elucidated.


We present a detailed investigation of hypoxia-inducible factor (HIF) 1 dependent gene expression in endothelial cells which suggests the importance of crosstalk between the peroxisome proliferator-activated receptor (PPAR) β/δ and HIF signaling axes. A migration assay shows a synergistic interaction between these two stimuli, and we identify angiopoietin-like 4 (ANGPTL4) as a common target gene by using a combination of microarray and ChIP-seq analysis. We profile changes of histone marks at enhancers under hypoxia, PPARβ/δ agonist and dual stimulations and these suggest that the spatial proximity of two response elements is the principal cause of the synergistic transcription induction. A newly developed quantitative chromosome conformation capture assay shows the quantitative change of the frequency of proximity of the two response elements.


To the best of our knowledge, this is the first report that two different transcription factors cooperate in transcriptional regulation in a synergistic fashion through conformational change of their common target genes.