YY1 directly interacts with myocardin to repress the triad myocardin/SRF/CArG box-mediated smooth muscle gene transcription during smooth muscle phenotypic modulation
Abstract Yin Yang 1 (YY1) regulates gene transcription in a variety of biological processes. In this study, we aim to determine the role of YY1 in vascular smooth muscle cell (VSMC) phenotypic modulation both in vivo and in vitro. Here we show that vascular injury in rodent carotid arteries induces...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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Nature Portfolio
2020-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-020-78544-3 |
| _version_ | 1818840187446231040 |
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| author | Jian-Pu Zheng Xiangqin He Fang Liu Shuping Yin Shichao Wu Maozhou Yang Jiawei Zhao Xiaohua Dai Hong Jiang Luyi Yu Qin Yin Donghong Ju Claire Li Leonard Lipovich Youming Xie Kezhong Zhang Hui J. Li Jiliang Zhou Li Li |
| author_facet | Jian-Pu Zheng Xiangqin He Fang Liu Shuping Yin Shichao Wu Maozhou Yang Jiawei Zhao Xiaohua Dai Hong Jiang Luyi Yu Qin Yin Donghong Ju Claire Li Leonard Lipovich Youming Xie Kezhong Zhang Hui J. Li Jiliang Zhou Li Li |
| author_sort | Jian-Pu Zheng |
| collection | DOAJ |
| description | Abstract Yin Yang 1 (YY1) regulates gene transcription in a variety of biological processes. In this study, we aim to determine the role of YY1 in vascular smooth muscle cell (VSMC) phenotypic modulation both in vivo and in vitro. Here we show that vascular injury in rodent carotid arteries induces YY1 expression along with reduced expression of smooth muscle differentiation markers in the carotids. Consistent with this finding, YY1 expression is induced in differentiated VSMCs in response to serum stimulation. To determine the underlying molecular mechanisms, we found that YY1 suppresses the transcription of CArG box-dependent SMC-specific genes including SM22α, SMα-actin and SMMHC. Interestingly, YY1 suppresses the transcriptional activity of the SM22α promoter by hindering the binding of serum response factor (SRF) to the proximal CArG box. YY1 also suppresses the transcription and the transactivation of myocardin (MYOCD), a master regulator for SMC-specific gene transcription by binding to SRF to form the MYOCD/SRF/CArG box triad (known as the ternary complex). Mechanistically, YY1 directly interacts with MYOCD to competitively displace MYOCD from SRF. This is the first evidence showing that YY1 inhibits SMC differentiation by directly targeting MYOCD. These findings provide new mechanistic insights into the regulatory mechanisms that govern SMC phenotypic modulation in the pathogenesis of vascular diseases. |
| first_indexed | 2024-12-19T04:06:12Z |
| format | Article |
| id | doaj.art-cc7f4842bb50449f8d66b93adfce802c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T04:06:12Z |
| publishDate | 2020-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-cc7f4842bb50449f8d66b93adfce802c2022-12-21T20:36:32ZengNature PortfolioScientific Reports2045-23222020-12-0110111510.1038/s41598-020-78544-3YY1 directly interacts with myocardin to repress the triad myocardin/SRF/CArG box-mediated smooth muscle gene transcription during smooth muscle phenotypic modulationJian-Pu Zheng0Xiangqin He1Fang Liu2Shuping Yin3Shichao Wu4Maozhou Yang5Jiawei Zhao6Xiaohua Dai7Hong Jiang8Luyi Yu9Qin Yin10Donghong Ju11Claire Li12Leonard Lipovich13Youming Xie14Kezhong Zhang15Hui J. Li16Jiliang Zhou17Li Li18Department of Internal Medicine, Wayne State UniversityDepartment of Pharmacology and Toxicology, Medical College of Georgia, Augusta UniversityDepartment of Pharmacology and Toxicology, Medical College of Georgia, Augusta UniversityDepartment of Internal Medicine, Wayne State UniversityDepartment of Internal Medicine, Wayne State UniversityBone and Joint Center, Henry Ford HospitalDepartment of Internal Medicine, Wayne State UniversityDepartment of Internal Medicine, Wayne State UniversityDepartment of Internal Medicine, Wayne State UniversityDepartment of Pharmacology and Toxicology, Medical College of Georgia, Augusta UniversityDepartment of Pharmacology and Toxicology, Medical College of Georgia, Augusta UniversityDepartment of Internal Medicine, Wayne State UniversityCenter for Molecular Medicine and Genetics, Wayne State UniversityCenter for Molecular Medicine and Genetics, Wayne State UniversityBarbara Ann Karmanos Cancer Institute, Wayne State UniversityCenter for Molecular Medicine and Genetics, Wayne State UniversityDepartment of Medicine, University of MassachusettsDepartment of Pharmacology and Toxicology, Medical College of Georgia, Augusta UniversityDepartment of Internal Medicine, Wayne State UniversityAbstract Yin Yang 1 (YY1) regulates gene transcription in a variety of biological processes. In this study, we aim to determine the role of YY1 in vascular smooth muscle cell (VSMC) phenotypic modulation both in vivo and in vitro. Here we show that vascular injury in rodent carotid arteries induces YY1 expression along with reduced expression of smooth muscle differentiation markers in the carotids. Consistent with this finding, YY1 expression is induced in differentiated VSMCs in response to serum stimulation. To determine the underlying molecular mechanisms, we found that YY1 suppresses the transcription of CArG box-dependent SMC-specific genes including SM22α, SMα-actin and SMMHC. Interestingly, YY1 suppresses the transcriptional activity of the SM22α promoter by hindering the binding of serum response factor (SRF) to the proximal CArG box. YY1 also suppresses the transcription and the transactivation of myocardin (MYOCD), a master regulator for SMC-specific gene transcription by binding to SRF to form the MYOCD/SRF/CArG box triad (known as the ternary complex). Mechanistically, YY1 directly interacts with MYOCD to competitively displace MYOCD from SRF. This is the first evidence showing that YY1 inhibits SMC differentiation by directly targeting MYOCD. These findings provide new mechanistic insights into the regulatory mechanisms that govern SMC phenotypic modulation in the pathogenesis of vascular diseases.https://doi.org/10.1038/s41598-020-78544-3 |
| spellingShingle | Jian-Pu Zheng Xiangqin He Fang Liu Shuping Yin Shichao Wu Maozhou Yang Jiawei Zhao Xiaohua Dai Hong Jiang Luyi Yu Qin Yin Donghong Ju Claire Li Leonard Lipovich Youming Xie Kezhong Zhang Hui J. Li Jiliang Zhou Li Li YY1 directly interacts with myocardin to repress the triad myocardin/SRF/CArG box-mediated smooth muscle gene transcription during smooth muscle phenotypic modulation Scientific Reports |
| title | YY1 directly interacts with myocardin to repress the triad myocardin/SRF/CArG box-mediated smooth muscle gene transcription during smooth muscle phenotypic modulation |
| title_full | YY1 directly interacts with myocardin to repress the triad myocardin/SRF/CArG box-mediated smooth muscle gene transcription during smooth muscle phenotypic modulation |
| title_fullStr | YY1 directly interacts with myocardin to repress the triad myocardin/SRF/CArG box-mediated smooth muscle gene transcription during smooth muscle phenotypic modulation |
| title_full_unstemmed | YY1 directly interacts with myocardin to repress the triad myocardin/SRF/CArG box-mediated smooth muscle gene transcription during smooth muscle phenotypic modulation |
| title_short | YY1 directly interacts with myocardin to repress the triad myocardin/SRF/CArG box-mediated smooth muscle gene transcription during smooth muscle phenotypic modulation |
| title_sort | yy1 directly interacts with myocardin to repress the triad myocardin srf carg box mediated smooth muscle gene transcription during smooth muscle phenotypic modulation |
| url | https://doi.org/10.1038/s41598-020-78544-3 |
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