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


RESULTS
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.


CONCLUSIONS
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.
Tsuyoshi
T
Inoue
Takahide
T
Kohro
Toshiya
T
Tanaka
Yasuharu
Y
Kanki
Guoliang
G
Li
Huay-Mei
HM
Poh
Imari
I
Mimura
Mika
M
Kobayashi
Akashi
A
Taguchi
Takashi
T
Maejima
Jun-ichi
J
Suehiro
Akira
A
Sugiyama
Kiyomi
K
Kaneki
Hirofumi
H
Aruga
Shoulian
S
Dong
Junko F
JF
Stevens
Shogo
S
Yamamoto
Shuichi
S
Tsutsumi
Toshiro
T
Fujita
Xiaoan
X
Ruan
Hiroyuki
H
Aburatani
Masaomi
M
Nangaku
Yijun
Y
Ruan
Tatsuhiko
T
Kodama
Youichiro
Y
Wada
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002843:Chromatin / Q000737:chemistry / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements
C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D002843:Chromatin; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047494:PPAR delta; D048068:PPAR-beta