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2017 ; 7
(1
): 1166
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Dynamics of chromatin accessibility during TGF-?-induced EMT of Ras-transformed
mammary gland epithelial cells
#MMPMID28446749
Arase M
; Tamura Y
; Kawasaki N
; Isogaya K
; Nakaki R
; Mizutani A
; Tsutsumi S
; Aburatani H
; Miyazono K
; Koinuma D
Sci Rep
2017[Apr]; 7
(1
): 1166
PMID28446749
show ga
Epithelial-mesenchymal transition (EMT) is induced by transforming growth factor
(TGF)-? and facilitates tumor progression. We here performed global mapping of
accessible chromatin in the mouse mammary gland epithelial EpH4 cell line and its
Ras-transformed derivative (EpRas) using formaldehyde-assisted isolation of
regulatory element (FAIRE)-sequencing. TGF-? and Ras altered chromatin
accessibility either cooperatively or independently, and AP1, ETS, and RUNX
binding motifs were enriched in the accessible chromatin regions of EpH4 and
EpRas cells. Etv4, an ETS family oncogenic transcription factor, was strongly
expressed and bound to more than one-third of the accessible chromatin regions in
EpRas cells treated with TGF-?. While knockdown of Etv4 and another ETS family
member Etv5 showed limited effects on the decrease in the E-cadherin abundance
and stress fiber formation by TGF-?, gene ontology analysis showed that genes
encoding extracellular proteins were most strongly down-regulated by Etv4 and
Etv5 siRNAs. Accordingly, TGF-?-induced expression of Mmp13 and cell invasiveness
were suppressed by Etv4 and Etv5 siRNAs, which were accompanied by the reduced
chromatin accessibility at an enhancer region of Mmp13 gene. These findings
suggest a mechanism of transcriptional regulation during Ras- and TGF-?-induced
EMT that involves alterations of accessible chromatin, which are partly regulated
by Etv4 and Etv5.