Circ‐myh8 Promotes Pulmonary Hypertension by Recruiting KAT7 to Govern Hypoxia‐Inducible Factor‐1α Expression
Background Aberrant expression of circular RNAs (circRNAs) contributes to the initiation and progression of pulmonary hypertension (PH). Hypoxia‐inducible factor (HIF) is a well‐known modulator of hypoxia‐induced PH. The role and underlying mechanism of circRNAs in the regulation of HIF expression r...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-04-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.122.028299 |
| _version_ | 1797825618605244416 |
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| author | Yan Xing Jing Qi Xiaohan Cheng Xinyue Song Jingya Zhang Songyue Li Xiaoting Zhao Ting Gong Jiaxin Yang Chong Zhao Wei Xin Daling Zhu Xiaodong Zheng |
| author_facet | Yan Xing Jing Qi Xiaohan Cheng Xinyue Song Jingya Zhang Songyue Li Xiaoting Zhao Ting Gong Jiaxin Yang Chong Zhao Wei Xin Daling Zhu Xiaodong Zheng |
| author_sort | Yan Xing |
| collection | DOAJ |
| description | Background Aberrant expression of circular RNAs (circRNAs) contributes to the initiation and progression of pulmonary hypertension (PH). Hypoxia‐inducible factor (HIF) is a well‐known modulator of hypoxia‐induced PH. The role and underlying mechanism of circRNAs in the regulation of HIF expression remains elusive. Methods and Results We profiled pulmonary artery transcriptomes using RNA sequencing and screened circRNAs associated with hypoxia treatment. The expression of a novel circRNA, circ_chr11_67292179–67294612 (circ‐myh8), was increased by hypoxia in a time‐dependent manner. We evaluated the effects of circ‐myh8 overexpression by adeno‐associated virus or inhibition by short hairpin RNA on proliferation and cell cycling in mice and pulmonary artery smooth muscle cells. Overexpression of circ‐myh8 promotes PH under normoxia, and disruption of circ‐myh8 by short hairpin RNA mitigates PH in chronic hypoxic mice. Biologically, circ‐myh8 induces the proliferation and cell‐cycle progression of pulmonary artery smooth muscle cells in vivo and in vitro. Mechanistically, RNA pull‐down and RNA immunoprecipitation assays were used to examine the interaction of circRNAs with the binding protein KAT7 (lysine acetyltransferase 7). The acetylation level of lysine 5 of histone H4 in the transcriptional initiation region of HIF1α was determined by chromatin immunoprecipitation assay followed by reverse transcription‐quantitative polymerase chain reaction. Circ‐myh8 acts as a modular scaffold to recruit histone acetyltransferase KAT7 to the promoters of HIF1α, which elicits acetylation of lysine 5 of histone H4 in their promoters. Conclusions Our findings not only reveal the pivotal roles of circ‐myh8 in governing histone modification in anti‐PH treatment but also advocate triggering the circ‐myh8/KAT7/HIF1α pathway to combat PH. |
| first_indexed | 2024-03-13T10:55:37Z |
| format | Article |
| id | doaj.art-bccb41265bec41658fc50e7b3787150e |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-13T10:55:37Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-bccb41265bec41658fc50e7b3787150e2023-05-17T04:33:58ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802023-04-0112710.1161/JAHA.122.028299Circ‐myh8 Promotes Pulmonary Hypertension by Recruiting KAT7 to Govern Hypoxia‐Inducible Factor‐1α ExpressionYan Xing0Jing Qi1Xiaohan Cheng2Xinyue Song3Jingya Zhang4Songyue Li5Xiaoting Zhao6Ting Gong7Jiaxin Yang8Chong Zhao9Wei Xin10Daling Zhu11Xiaodong Zheng12Department of Pharmacology Harbin Medical University–Daqing Daqing Heilongjiang ChinaDepartment of Pharmacology Harbin Medical University–Daqing Daqing Heilongjiang ChinaSchool of Pharmacy Harbin Medical University–Daqing Daqing Heilongjiang ChinaCollege of Pharmacy, Harbin Medical University Harbin ChinaDepartment of Pharmacology Harbin Medical University–Daqing Daqing Heilongjiang ChinaDepartment of Pharmacology Harbin Medical University–Daqing Daqing Heilongjiang ChinaDepartment of Medical Genetics Harbin Medical University–Daqing Daqing Heilongjiang ChinaDepartment of Medical Genetics Harbin Medical University–Daqing Daqing Heilongjiang ChinaDepartment of Medical Genetics Harbin Medical University–Daqing Daqing Heilongjiang ChinaLibrary of Harbin Medical University–Daqing Daqing Heilongjiang ChinaCollege of Pharmacy, Harbin Medical University Harbin ChinaCollege of Pharmacy, Harbin Medical University Harbin ChinaDepartment of Medical Genetics Harbin Medical University–Daqing Daqing Heilongjiang ChinaBackground Aberrant expression of circular RNAs (circRNAs) contributes to the initiation and progression of pulmonary hypertension (PH). Hypoxia‐inducible factor (HIF) is a well‐known modulator of hypoxia‐induced PH. The role and underlying mechanism of circRNAs in the regulation of HIF expression remains elusive. Methods and Results We profiled pulmonary artery transcriptomes using RNA sequencing and screened circRNAs associated with hypoxia treatment. The expression of a novel circRNA, circ_chr11_67292179–67294612 (circ‐myh8), was increased by hypoxia in a time‐dependent manner. We evaluated the effects of circ‐myh8 overexpression by adeno‐associated virus or inhibition by short hairpin RNA on proliferation and cell cycling in mice and pulmonary artery smooth muscle cells. Overexpression of circ‐myh8 promotes PH under normoxia, and disruption of circ‐myh8 by short hairpin RNA mitigates PH in chronic hypoxic mice. Biologically, circ‐myh8 induces the proliferation and cell‐cycle progression of pulmonary artery smooth muscle cells in vivo and in vitro. Mechanistically, RNA pull‐down and RNA immunoprecipitation assays were used to examine the interaction of circRNAs with the binding protein KAT7 (lysine acetyltransferase 7). The acetylation level of lysine 5 of histone H4 in the transcriptional initiation region of HIF1α was determined by chromatin immunoprecipitation assay followed by reverse transcription‐quantitative polymerase chain reaction. Circ‐myh8 acts as a modular scaffold to recruit histone acetyltransferase KAT7 to the promoters of HIF1α, which elicits acetylation of lysine 5 of histone H4 in their promoters. Conclusions Our findings not only reveal the pivotal roles of circ‐myh8 in governing histone modification in anti‐PH treatment but also advocate triggering the circ‐myh8/KAT7/HIF1α pathway to combat PH.https://www.ahajournals.org/doi/10.1161/JAHA.122.028299circular RNAhistone modificationKAT7pulmonary hypertension |
| spellingShingle | Yan Xing Jing Qi Xiaohan Cheng Xinyue Song Jingya Zhang Songyue Li Xiaoting Zhao Ting Gong Jiaxin Yang Chong Zhao Wei Xin Daling Zhu Xiaodong Zheng Circ‐myh8 Promotes Pulmonary Hypertension by Recruiting KAT7 to Govern Hypoxia‐Inducible Factor‐1α Expression Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease circular RNA histone modification KAT7 pulmonary hypertension |
| title | Circ‐myh8 Promotes Pulmonary Hypertension by Recruiting KAT7 to Govern Hypoxia‐Inducible Factor‐1α Expression |
| title_full | Circ‐myh8 Promotes Pulmonary Hypertension by Recruiting KAT7 to Govern Hypoxia‐Inducible Factor‐1α Expression |
| title_fullStr | Circ‐myh8 Promotes Pulmonary Hypertension by Recruiting KAT7 to Govern Hypoxia‐Inducible Factor‐1α Expression |
| title_full_unstemmed | Circ‐myh8 Promotes Pulmonary Hypertension by Recruiting KAT7 to Govern Hypoxia‐Inducible Factor‐1α Expression |
| title_short | Circ‐myh8 Promotes Pulmonary Hypertension by Recruiting KAT7 to Govern Hypoxia‐Inducible Factor‐1α Expression |
| title_sort | circ myh8 promotes pulmonary hypertension by recruiting kat7 to govern hypoxia inducible factor 1α expression |
| topic | circular RNA histone modification KAT7 pulmonary hypertension |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.122.028299 |
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