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dc.contributor.authorHe, Mingen_US
dc.contributor.authorHuang, Tse-Shunen_US
dc.contributor.authorLi, Shuaien_US
dc.contributor.authorHong, Hsiao-Chinen_US
dc.contributor.authorChen, Zhenen_US
dc.contributor.authorMartin, Marcyen_US
dc.contributor.authorZhou, Xinen_US
dc.contributor.authorHuang, Hsi-Yuanen_US
dc.contributor.authorSu, Shu-Hanen_US
dc.contributor.authorZhang, Jiaoen_US
dc.contributor.authorWang, Wei-Tingen_US
dc.contributor.authorKang, Jianen_US
dc.contributor.authorHuang, Hsien-Daen_US
dc.contributor.authorZhang, Jinen_US
dc.contributor.authorChien, Shuen_US
dc.contributor.authorShyy, John Y. -J.en_US
dc.date.accessioned2019-06-03T01:08:31Z-
dc.date.available2019-06-03T01:08:31Z-
dc.date.issued2019-05-01en_US
dc.identifier.issn1079-5642en_US
dc.identifier.urihttp://dx.doi.org/10.1161/ATVBAHA.118.312301en_US
dc.identifier.urihttp://hdl.handle.net/11536/151911-
dc.description.abstractObjective-The topographical distribution of atherosclerosis in vasculature underscores the importance of shear stress inregulating endothelium. With a systems approach integrating sequencing data, the current study aims to explore the link between shear stress-regulated master transcription factor and its regulation of endothelial cell (EC) function via epigenetic modifications. Approach and Results-H3K27ac (acetylation of histone 3 lysine 27)-ChIP-seq (chromatin immunoprecipitation followed by high throughput sequencing), ATAC-seq (an assay for transposase-accessible chromatin-sequencing), and RNAseq (RNA-sequencing) were performed to investigate the genome-wide epigenetic regulations in ECs in response to atheroprotective pulsatile shear stress (PS). In silico prediction revealed that KLF4 binding motifs were enriched in the PS-enhanced H3K27ac regions. By integrating PS-and KLF4-modulated H3K27ac, we identified 18 novel PS-upregulated genes. The promoter regions of these genes showed an overlap between the KLF4-enhanced assay for transposase-accessible chromatin signals and the PS-induced H3K27ac peaks. Experiments using ECs isolated from mouse aorta, lung ECs from EC-KLF4-TG versus EC-KLF4-KO mice, and atorvastatin-treated ECs showed that ITPR3 (inositol 1,4,5-trisphosphate receptor 3) was robustly activated by KLF4 and statins. KLF4 ATAC-qPCR (quantitative polymerase chain reaction) and ChIP-qPCR further demonstrated that a specific locus in the promoter region of the ITPR3 gene was essential for KLF4 binding, H3K27ac enrichment, chromatin accessibility, RNA polymerase II recruitment, and ITPR3 transcriptional activation. Deletion of this KLF4 binding locus in ECs by using CRISPR-Cas9 resulted in blunted calcium influx, reduced expression of endothelial nitric oxide synthase, and diminished nitric oxide bioavailability. Conclusions-These results from a novel multiomics study suggest that KLF4 is crucial for PS-modulated H3K27ac that allow the transcriptional activation of ITPR3. This novel mechanism contributes to the Ca2+-dependent eNOS (endothelial nitric oxide synthase) activation and EC homeostasis.en_US
dc.language.isoen_USen_US
dc.subjectendothelial cellsen_US
dc.subjectgenomeen_US
dc.subjecthistonesen_US
dc.subjectnitric oxideen_US
dc.subjectshear stressen_US
dc.titleAtheroprotective Flow Upregulates ITPR3 (Inositol 1,4,5-Trisphosphate Receptor 3) in Vascular Endothelium via KLF4 (Kruppel-Like Factor 4)-Mediated Histone Modificationsen_US
dc.typeArticleen_US
dc.identifier.doi10.1161/ATVBAHA.118.312301en_US
dc.identifier.journalARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGYen_US
dc.citation.volume39en_US
dc.citation.issue5en_US
dc.citation.spage902en_US
dc.citation.epage914en_US
dc.contributor.department生物科技學系zh_TW
dc.contributor.department生物資訊及系統生物研究所zh_TW
dc.contributor.departmentDepartment of Biological Science and Technologyen_US
dc.contributor.departmentInstitude of Bioinformatics and Systems Biologyen_US
dc.identifier.wosnumberWOS:000465419100012en_US
dc.citation.woscount0en_US
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