Transcriptomics

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IL-4 mediated gene expression profiles in vascular endothelial cells


ABSTRACT: Endothelial cell activation and dysfunction underlie many vascular disorders, including atherosclerosis and inflammation. Here, we show that interleukin (IL)-4 markedly induced vascular cell adhesion molecule (VCAM)-1, both in cultured endothelial cells and in the intact endothelium in mice. Combined treatment with IL-4 and tumor necrosis factor (TNF)- alpha resulted in further, sustained induction of VCAM-1 expression. IL-4-mediated induction of VCAM-1 and secondary monocyte adhesion was predominantly regulated by the transcription factor, STAT6. Genome-wide survey of IL-4-mediated STAT6 binding from sequential chromatin-immunoprecipitation with deep-sequencing (ChIP-seq) in endothelial cells revealed regions of transient and sustained transcription factor binding. By combining DNA microarrays and ChIP-seq at the same time points, the majority of IL-4-responsive genes were shown to be STAT6-dependent and associated with direct STAT6 binding to their promoter. IL-4-mediated stable binding of STAT6 led to sustained target gene expression. Moreover, our strategy led to the identification of a novel functionally important STAT6 binding site within -16 kb upstream of the VCAM-1 gene. Taken together, these findings support a critical role for STAT6 in mediating IL-4 signal transduction in endothelial cells. Identification of a novel IL-4-mediated VCAM-1 enhancer may provide a foundation for targeted therapy in vascular disease (ChIP-seq data not submitted to GEO). Total 13 samples were derived from [1] HUVEC treated in the absence (0h) or presence of IL-4 (1,2,4,8, and 16h) to determine IL-4 regulated gene in endotherial cells, [2] control-siRNA or si-STAT6 transfected HUVEC cells treated in the absence or presenceof IL-4 [3] Ad-control or Ad-CA-STAT6 transfected HUVEC cells for the identification of STAT-6 dependent genes in endothelial cells.

ORGANISM(S): Homo sapiens  

SUBMITTER: Hideto Tozawa  Shuichi Tsutsumi   Takahide Kohro   Tatsuhiko Kodama   Jun-ichi Suehiro   Takashi Minami   Hiroyuki Aburatani   Yasuharu Kanki    

PROVIDER: E-GEOD-28117 | ArrayExpress | 2011-05-01

SECONDARY ACCESSION(S): GSE28117PRJNA139837

REPOSITORIES: GEO, ArrayExpress

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Publications

Genome-wide approaches reveal functional interleukin-4-inducible STAT6 binding to the vascular cell adhesion molecule 1 promoter.

Tozawa Hideto H   Kanki Yasuharu Y   Suehiro Jun-ichi J   Tsutsumi Shuichi S   Kohro Takahide T   Wada Youichiro Y   Aburatani Hiroyuki H   Aird William C WC   Kodama Tatsuhiko T   Minami Takashi T  

Molecular and cellular biology 20110404 11


Endothelial cell activation and dysfunction underlie many vascular disorders, including atherosclerosis and inflammation. Here, we show that interleukin-4 (IL-4) markedly induced vascular cell adhesion molecule 1 (VCAM-1), both in cultured endothelial cells and in the intact endothelium in mice. Combined treatment with IL-4 and tumor necrosis factor alpha (TNF-α) resulted in further, sustained induction of VCAM-1 expression. IL-4-mediated induction of VCAM-1 and secondary monocyte adhesion was p  ...[more]

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