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KMID : 1034820230190010119
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Molecular & Cellular Toxicology
2023 Volume.19 No. 1 p.119 ~ p.133
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CTCF-mediated H3K27me3 enrichment on the LncRNA MALAT1 promoter regulates the cardiomyocytes from I/R-induced apoptosis through targeting miR-26b-5p
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Yanhong Yang
Zhiyong Chen
Huan Le
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Abstract
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Background : It is reported that LncRNAs play an important role in various diseases, including myocardial ischemia?reperfusion injury. However, the regulatory mechanism of LncRNAs in I/R injury of cardiac has not been fully elucidated.
Objective : This study aimed to explore the interaction of LncRNA MALAT1 and aberrant histone modification in I/R injury cardiomyocytes.
Results : After myocardial I/R or H/R injury, the expression level of CTCF was up-regulated and MALAT1 was down-regulated. Silencing of CTCF promoted the cardiomyocytes survival and apoptosis after H/R treatment. Moreover, the expression of H3K27me3 was significantly inhibited by CTCF down-regulation. H3K27me3 protein could directly bind to the promoter of MALAT1. In addition, we found that the inhibition CTCF could up-regulate the expression of MALAT1 in cardiomyocytes. In addition, down-regulation of MALAT1 could reverse the effects of silencing of CTCF on cardiomyocytes growth and apoptosis in H/R injury. Furthermore, the bioinformatic analysis showed 12 potential targets, while only miR-26b-5p could directly bind with MALAT1. The inhibition of CTCF repressed the miR-26b-5p expression and the silencing of MALAT1 promoted miR-26b-5p expression. Besides, the miR-26b-5p was decreased in cardiomyocytes under H/R treatment. Overexpression of MALAT1 significantly promoted cardiomyocytes cell growth and repressed cell apoptosis, while the miR-26b-5p reversed these effects. In myocardial I/R injury mice model, overexpression of MALAT1 alleviated the myocardial tissue injury and repressed the H3K27me3 level, however, all those effects were reversed by CTCF.
Conclusions : CTCF was highly expressed in H/R cardiomyocytes and I/R myocardial tissue and the silencing of CTCF-mediated H3K27me3 dissociating from the MALAT1 promoter to regulate cardiomyocytes survival and apoptosis by targeting miR-26b-5p. It provided a new therapeutic marker for myocardial I/R injury.
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KEYWORD
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LncRNA MALAT1, Myocardial I/R injury, H3K27me3, CTCF, MiR-26b-5p, Cell survival and apoptosis
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