Academic Journal
Inhibition of DYRK1A, via histone modification, promotes cardiomyocyte cell cycle activation and cardiac repair after myocardial infarction
| العنوان: | Inhibition of DYRK1A, via histone modification, promotes cardiomyocyte cell cycle activation and cardiac repair after myocardial infarction |
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| المؤلفون: | Cong Lan, Caiyu Chen, Shuang Qu, Nian Cao, Hao Luo, Cheng Yu, Na Wang, Yuanzheng Xue, Xuewei Xia, Chao Fan, Hongmei Ren, Yongjian Yang, Pedro A. Jose, Zaicheng Xu, Gengze Wu, Chunyu Zeng |
| المصدر: | EBioMedicine, Vol 82, Iss , Pp 104139- (2022) |
| بيانات النشر: | Elsevier, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Medicine LCC:Medicine (General) |
| مصطلحات موضوعية: | Cardiomyocyte cell cycle activation, Cardiac repair, DYRK1A, H3K27ac, H3K4me3, Medicine, Medicine (General), R5-920 |
| الوصف: | Summary: Background: While the adult mammalian heart undergoes only modest renewal through cardiomyocyte proliferation, boosting this process is considered a promising therapeutic strategy to repair cardiac injury. This study explored the role and mechanism of dual-specificity tyrosine regulated kinase 1A (DYRK1A) in regulating cardiomyocyte cell cycle activation and cardiac repair after myocardial infarction (MI). Methods: DYRK1A-knockout mice and DYRK1A inhibitors were used to investigate the role of DYRK1A in cardiomyocyte cell cycle activation and cardiac repair following MI. Additionally, we explored the underlying mechanisms by combining genome-wide transcriptomic, epigenomic, and proteomic analyses. Findings: In adult mice subjected to MI, both conditional deletion and pharmacological inhibition of DYRK1A induced cardiomyocyte cell cycle activation and cardiac repair with improved cardiac function. Combining genome-wide transcriptomic and epigenomic analyses revealed that DYRK1A knockdown resulted in robust cardiomyocyte cell cycle activation (shown by the enhanced expression of many genes governing cell proliferation) associated with increased deposition of trimethylated histone 3 Lys4 (H3K4me3) and acetylated histone 3 Lys27 (H3K27ac) on the promoter regions of these genes. Mechanistically, via unbiased mass spectrometry, we discovered that WD repeat-containing protein 82 and lysine acetyltransferase 6A were key mediators in the epigenetic modification of H3K4me3 and H3K27ac and subsequent pro-proliferative transcriptome and cardiomyocyte cell cycle activation. Interpretation: Our results reveal a significant role of DYRK1A in cardiac repair and suggest a drug target with translational potential for treating cardiomyopathy. Funding: This study was supported in part by grants from the National Natural Science Foundation of China (81930008, 82022005, 82070296, 82102834), National Key R&D Program of China (2018YFC1312700), Program of Innovative Research Team by the National Natural Science Foundation (81721001), and National Institutes of Health (5R01DK039308-31, 7R37HL023081-37, 5P01HL074940-11). |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2352-3964 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2352396422003206; https://doaj.org/toc/2352-3964 |
| DOI: | 10.1016/j.ebiom.2022.104139 |
| URL الوصول: | https://doaj.org/article/0ab13c40c0504d0a8ca022039d351474 |
| رقم الانضمام: | edsdoj.0ab13c40c0504d0a8ca022039d351474 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 23523964 |
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| DOI: | 10.1016/j.ebiom.2022.104139 |