Histone methyltransferase KMT2D contributes to the protection of myocardial ischemic injury
Histone H3 lysine 4 (H3K4) methyltransferase 2D (KMT2D) plays an important role in cell development in early life. However, the function of KMT2D in adult cells such as cardiomyocytes or neurons has not been reported. In this study, cardiomyocyte-specific KMT2D knockout (KMT2D-cKO) and control (KMT2...
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.946484/full |
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| author | Shu-Bao Liu Xiang-Min Meng Yu-Meng Li Jun-Meng Wang Hui-Hui Guo Chaochen Wang Bing-Mei Zhu |
| author_facet | Shu-Bao Liu Xiang-Min Meng Yu-Meng Li Jun-Meng Wang Hui-Hui Guo Chaochen Wang Bing-Mei Zhu |
| author_sort | Shu-Bao Liu |
| collection | DOAJ |
| description | Histone H3 lysine 4 (H3K4) methyltransferase 2D (KMT2D) plays an important role in cell development in early life. However, the function of KMT2D in adult cells such as cardiomyocytes or neurons has not been reported. In this study, cardiomyocyte-specific KMT2D knockout (KMT2D-cKO) and control (KMT2D-Ctl) mice were exposed to sham or myocardial ischemia (MI) surgery. Depletion of KMT2D aggravated the ischemic area, led to the increased mortality (26.5% in KMT2D-cKO vs 12.5% in KMT2D-Ctl) of the mice, and weakened the left ventricular systolic function. RNA-seq analysis in cardiac tissues identified genes whose expression was changed by MI and KMT2D deletion. Combined with the genome-wide association study (GWAS) analysis, cardiac disease-associated genes Rasd1, Thsd7a, Ednra, and Tns1 were identified. The expression of the Rasd1 was significantly decreased by MI or the loss of KMT2D in vivo. Meanwhile, ChIP assays demonstrated that either MI or loss of KMT2D attenuated monomethylated H3K4 (H3K4me1) enrichment on the enhancer of Rasd1. By generating a KMT2D knockout (H9C2-KO) H9C2 monoclone, we verified that the expression of Rasd1 was controlled by KMT2D, and the expression of Rasd1 was decreased by serum starvation but not low-(O2) treatment in H9C2 cells. KMT2D has a protective effect on ischemic myocardium by regulating cardiac disease-associated genes including Rasd1. KMT2D is required for the H3K4me1 deposition on the enhancer of Rasd1. Our data for the first time suggest that KMT2D-mediated Rasd1 expression may play an important protective effect on adult cells during nutritional deficiency caused by ischemic injury. |
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| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-10T09:12:42Z |
| publishDate | 2022-07-01 |
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| spelling | doaj.art-87ca8f7ed5884cb7819c9cccaacb28d12022-12-22T01:54:58ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-07-011010.3389/fcell.2022.946484946484Histone methyltransferase KMT2D contributes to the protection of myocardial ischemic injuryShu-Bao Liu0Xiang-Min Meng1Yu-Meng Li2Jun-Meng Wang3Hui-Hui Guo4Chaochen Wang5Bing-Mei Zhu6Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, ChinaRegenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, ChinaRegenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, ChinaKey Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaKey Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaZhejiang University-University of Edinburgh Institute, International Campus, Zhejiang University, Haining, Zhejiang, ChinaRegenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, ChinaHistone H3 lysine 4 (H3K4) methyltransferase 2D (KMT2D) plays an important role in cell development in early life. However, the function of KMT2D in adult cells such as cardiomyocytes or neurons has not been reported. In this study, cardiomyocyte-specific KMT2D knockout (KMT2D-cKO) and control (KMT2D-Ctl) mice were exposed to sham or myocardial ischemia (MI) surgery. Depletion of KMT2D aggravated the ischemic area, led to the increased mortality (26.5% in KMT2D-cKO vs 12.5% in KMT2D-Ctl) of the mice, and weakened the left ventricular systolic function. RNA-seq analysis in cardiac tissues identified genes whose expression was changed by MI and KMT2D deletion. Combined with the genome-wide association study (GWAS) analysis, cardiac disease-associated genes Rasd1, Thsd7a, Ednra, and Tns1 were identified. The expression of the Rasd1 was significantly decreased by MI or the loss of KMT2D in vivo. Meanwhile, ChIP assays demonstrated that either MI or loss of KMT2D attenuated monomethylated H3K4 (H3K4me1) enrichment on the enhancer of Rasd1. By generating a KMT2D knockout (H9C2-KO) H9C2 monoclone, we verified that the expression of Rasd1 was controlled by KMT2D, and the expression of Rasd1 was decreased by serum starvation but not low-(O2) treatment in H9C2 cells. KMT2D has a protective effect on ischemic myocardium by regulating cardiac disease-associated genes including Rasd1. KMT2D is required for the H3K4me1 deposition on the enhancer of Rasd1. Our data for the first time suggest that KMT2D-mediated Rasd1 expression may play an important protective effect on adult cells during nutritional deficiency caused by ischemic injury.https://www.frontiersin.org/articles/10.3389/fcell.2022.946484/fullmethyltransferaseserumtranscriptional regulationglucocorticoid response elementischemia |
| spellingShingle | Shu-Bao Liu Xiang-Min Meng Yu-Meng Li Jun-Meng Wang Hui-Hui Guo Chaochen Wang Bing-Mei Zhu Histone methyltransferase KMT2D contributes to the protection of myocardial ischemic injury Frontiers in Cell and Developmental Biology methyltransferase serum transcriptional regulation glucocorticoid response element ischemia |
| title | Histone methyltransferase KMT2D contributes to the protection of myocardial ischemic injury |
| title_full | Histone methyltransferase KMT2D contributes to the protection of myocardial ischemic injury |
| title_fullStr | Histone methyltransferase KMT2D contributes to the protection of myocardial ischemic injury |
| title_full_unstemmed | Histone methyltransferase KMT2D contributes to the protection of myocardial ischemic injury |
| title_short | Histone methyltransferase KMT2D contributes to the protection of myocardial ischemic injury |
| title_sort | histone methyltransferase kmt2d contributes to the protection of myocardial ischemic injury |
| topic | methyltransferase serum transcriptional regulation glucocorticoid response element ischemia |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.946484/full |
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