A hierarchical and collaborative BRD4/CEBPD partnership governs vascular smooth muscle cell inflammation
Bromodomain protein BRD4 reads histone acetylation (H3K27ac), an epigenomic mark of transcription enhancers. CCAAT enhancer binding protein delta (CEBPD) is a transcription factor typically studied in metabolism. While both are potent effectors and potential therapeutic targets, their relationship w...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S232905012100036X |
| _version_ | 1818671824412606464 |
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| author | Qingwei Wang Hatice Gulcin Ozer Bowen Wang Mengxue Zhang Go Urabe Yitao Huang K. Craig Kent Lian-Wang Guo |
| author_facet | Qingwei Wang Hatice Gulcin Ozer Bowen Wang Mengxue Zhang Go Urabe Yitao Huang K. Craig Kent Lian-Wang Guo |
| author_sort | Qingwei Wang |
| collection | DOAJ |
| description | Bromodomain protein BRD4 reads histone acetylation (H3K27ac), an epigenomic mark of transcription enhancers. CCAAT enhancer binding protein delta (CEBPD) is a transcription factor typically studied in metabolism. While both are potent effectors and potential therapeutic targets, their relationship was previously unknown. Here we investigated their interplay in vascular smooth muscle cell (SMC) inflammation. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) revealed H3K27ac/BRD4 enrichment at Cebpd in injured rat carotid arteries. While genomic deletion of BRD4-associated enhancer in SMCs in vitro decreased Cebpd transcripts, BRD4 gene silencing also diminished Cebpd mRNA and protein, indicative of a BRD4 control over CEBPD expression. Bromodomain-1, but not bromodomain-2, accounted for this BRD4 function. Moreover, endogenous BRD4 protein co-immunoprecipitated with CEBPD, and both proteins co-immunoprecipitated the Cebpd promoter and enhancer DNA fragments. These co-immunoprecipitations (coIPs) were all abolished by the BRD4-bromodomain blocker JQ1, suggesting a BRD4/CEBPD /promoter/enhancer complex. While BRD4 and CEBPD were both upregulated upon tumor necrosis factor alpha (TNF-α) stimulation of SMC inflammation (increased interleukin [IL]-1b, IL-6, and MCP-1), they mediated this stimulation via preferentially elevated expression of platelet-derived growth factor receptor alpha (PDGFRα, versus PDGFRβ), as indicated by loss- and gain-of-function experiments. Taken together, our study unravels a hierarchical yet collaborative BRD4/CEBPD relationship, a previously unrecognized mechanism that prompts SMC inflammation and may underlie other pathophysiological processes as well. |
| first_indexed | 2024-12-17T07:30:08Z |
| format | Article |
| id | doaj.art-c4501990cf32428e9ba19ad13169e516 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-17T07:30:08Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-c4501990cf32428e9ba19ad13169e5162022-12-21T21:58:31ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012021-06-01215466A hierarchical and collaborative BRD4/CEBPD partnership governs vascular smooth muscle cell inflammationQingwei Wang0Hatice Gulcin Ozer1Bowen Wang2Mengxue Zhang3Go Urabe4Yitao Huang5K. Craig Kent6Lian-Wang Guo7Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USADepartment of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USADepartment of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA; Corresponding author: Lian-Wang Guo, PhD, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.Bromodomain protein BRD4 reads histone acetylation (H3K27ac), an epigenomic mark of transcription enhancers. CCAAT enhancer binding protein delta (CEBPD) is a transcription factor typically studied in metabolism. While both are potent effectors and potential therapeutic targets, their relationship was previously unknown. Here we investigated their interplay in vascular smooth muscle cell (SMC) inflammation. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) revealed H3K27ac/BRD4 enrichment at Cebpd in injured rat carotid arteries. While genomic deletion of BRD4-associated enhancer in SMCs in vitro decreased Cebpd transcripts, BRD4 gene silencing also diminished Cebpd mRNA and protein, indicative of a BRD4 control over CEBPD expression. Bromodomain-1, but not bromodomain-2, accounted for this BRD4 function. Moreover, endogenous BRD4 protein co-immunoprecipitated with CEBPD, and both proteins co-immunoprecipitated the Cebpd promoter and enhancer DNA fragments. These co-immunoprecipitations (coIPs) were all abolished by the BRD4-bromodomain blocker JQ1, suggesting a BRD4/CEBPD /promoter/enhancer complex. While BRD4 and CEBPD were both upregulated upon tumor necrosis factor alpha (TNF-α) stimulation of SMC inflammation (increased interleukin [IL]-1b, IL-6, and MCP-1), they mediated this stimulation via preferentially elevated expression of platelet-derived growth factor receptor alpha (PDGFRα, versus PDGFRβ), as indicated by loss- and gain-of-function experiments. Taken together, our study unravels a hierarchical yet collaborative BRD4/CEBPD relationship, a previously unrecognized mechanism that prompts SMC inflammation and may underlie other pathophysiological processes as well.http://www.sciencedirect.com/science/article/pii/S232905012100036XBRD4CEBPDChIP sequencingvascular smooth muscle cell state transition |
| spellingShingle | Qingwei Wang Hatice Gulcin Ozer Bowen Wang Mengxue Zhang Go Urabe Yitao Huang K. Craig Kent Lian-Wang Guo A hierarchical and collaborative BRD4/CEBPD partnership governs vascular smooth muscle cell inflammation Molecular Therapy: Methods & Clinical Development BRD4 CEBPD ChIP sequencing vascular smooth muscle cell state transition |
| title | A hierarchical and collaborative BRD4/CEBPD partnership governs vascular smooth muscle cell inflammation |
| title_full | A hierarchical and collaborative BRD4/CEBPD partnership governs vascular smooth muscle cell inflammation |
| title_fullStr | A hierarchical and collaborative BRD4/CEBPD partnership governs vascular smooth muscle cell inflammation |
| title_full_unstemmed | A hierarchical and collaborative BRD4/CEBPD partnership governs vascular smooth muscle cell inflammation |
| title_short | A hierarchical and collaborative BRD4/CEBPD partnership governs vascular smooth muscle cell inflammation |
| title_sort | hierarchical and collaborative brd4 cebpd partnership governs vascular smooth muscle cell inflammation |
| topic | BRD4 CEBPD ChIP sequencing vascular smooth muscle cell state transition |
| url | http://www.sciencedirect.com/science/article/pii/S232905012100036X |
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