Inhibition of the cardiac fibroblast-enriched histone methyltransferase Dot1L prevents cardiac fibrosis and cardiac dysfunction
Abstract Background Cardiac fibrosis is characterized by excessive extracellular matrix deposition that contributes to compromised cardiac function and potentially heart failure. Disruptor of telomeric silencing 1-like (Dot1L) is the catalytic enzyme required for histone H3K79 methylation which has...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-08-01
|
| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13578-022-00877-5 |
| _version_ | 1818517306778583040 |
|---|---|
| author | Jie Xu Jinghuan Wang Fen Long Wen Zhong Haibi Su Zhenghua Su Xinhua Liu |
| author_facet | Jie Xu Jinghuan Wang Fen Long Wen Zhong Haibi Su Zhenghua Su Xinhua Liu |
| author_sort | Jie Xu |
| collection | DOAJ |
| description | Abstract Background Cardiac fibrosis is characterized by excessive extracellular matrix deposition that contributes to compromised cardiac function and potentially heart failure. Disruptor of telomeric silencing 1-like (Dot1L) is the catalytic enzyme required for histone H3K79 methylation which has been demonstrated to play a role in transcriptional activation. However, the functions of Dot1L in the process of cardiac fibrosis still remain unknown. Results In the present study, we found that endogenous Dot1L is upregulated in cardiac fibroblasts (CFs) treated with angiotensin II (Ang II) or transforming growth factor (TGF)-β1, along with elevated extracellular matrix (ECM) such as fibronectin, collagen I and III. Silencing or inhibiting Dot1L mitigated Ang II-induced myofibroblast generation and fibrogenesis. We identified the transcription factor-forkhead box O (FoxO) 3a as a novel substrate of Dot1L, the transcriptional activating mark H3K79me3 level on the promoter of FoxO3a was increase in activated-CFs, and inhibition of Dot1L markedly decreased FoxO3a transcription accompanied by a significant decrease in the expression of fibrogenic gene. Knockdown of FoxO3a could alleviate ECM deposition induced by Ang II, on the contrary, overexpression FoxO3a resulting in CFs activation. Consistently, in vivo Dot1L ablation rescued myocardial ischemia-induced cardiac fibrosis and improved cardiac function. Conclusions Our findings conclude that upregulation of Dot1L results in activation of the cardiac fibroblasts to promote profibrotic gene, eventually causes cardiac fibrosis. Pharmacological targeting for Dot1L might represent a promising therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases. |
| first_indexed | 2024-12-11T00:54:30Z |
| format | Article |
| id | doaj.art-55e56bfb2bae47a98f58a0c700f40374 |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-12-11T00:54:30Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-55e56bfb2bae47a98f58a0c700f403742022-12-22T01:26:31ZengBMCCell & Bioscience2045-37012022-08-0112111610.1186/s13578-022-00877-5Inhibition of the cardiac fibroblast-enriched histone methyltransferase Dot1L prevents cardiac fibrosis and cardiac dysfunctionJie Xu0Jinghuan Wang1Fen Long2Wen Zhong3Haibi Su4Zhenghua Su5Xinhua Liu6School of Pharmacy, Pharmacophenomics Laboratory, Human Phenome Institute, Fudan UniversitySchool of Pharmacy, Pharmacophenomics Laboratory, Human Phenome Institute, Fudan UniversitySchool of Pharmacy, Pharmacophenomics Laboratory, Human Phenome Institute, Fudan UniversitySchool of Pharmacy, Pharmacophenomics Laboratory, Human Phenome Institute, Fudan UniversitySchool of Pharmacy, Pharmacophenomics Laboratory, Human Phenome Institute, Fudan UniversitySchool of Pharmacy, Pharmacophenomics Laboratory, Human Phenome Institute, Fudan UniversitySchool of Pharmacy, Pharmacophenomics Laboratory, Human Phenome Institute, Fudan UniversityAbstract Background Cardiac fibrosis is characterized by excessive extracellular matrix deposition that contributes to compromised cardiac function and potentially heart failure. Disruptor of telomeric silencing 1-like (Dot1L) is the catalytic enzyme required for histone H3K79 methylation which has been demonstrated to play a role in transcriptional activation. However, the functions of Dot1L in the process of cardiac fibrosis still remain unknown. Results In the present study, we found that endogenous Dot1L is upregulated in cardiac fibroblasts (CFs) treated with angiotensin II (Ang II) or transforming growth factor (TGF)-β1, along with elevated extracellular matrix (ECM) such as fibronectin, collagen I and III. Silencing or inhibiting Dot1L mitigated Ang II-induced myofibroblast generation and fibrogenesis. We identified the transcription factor-forkhead box O (FoxO) 3a as a novel substrate of Dot1L, the transcriptional activating mark H3K79me3 level on the promoter of FoxO3a was increase in activated-CFs, and inhibition of Dot1L markedly decreased FoxO3a transcription accompanied by a significant decrease in the expression of fibrogenic gene. Knockdown of FoxO3a could alleviate ECM deposition induced by Ang II, on the contrary, overexpression FoxO3a resulting in CFs activation. Consistently, in vivo Dot1L ablation rescued myocardial ischemia-induced cardiac fibrosis and improved cardiac function. Conclusions Our findings conclude that upregulation of Dot1L results in activation of the cardiac fibroblasts to promote profibrotic gene, eventually causes cardiac fibrosis. Pharmacological targeting for Dot1L might represent a promising therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases.https://doi.org/10.1186/s13578-022-00877-5Dot1LCardiac FibrosisCardiac fibroblastsCardiac functionFoxO3a |
| spellingShingle | Jie Xu Jinghuan Wang Fen Long Wen Zhong Haibi Su Zhenghua Su Xinhua Liu Inhibition of the cardiac fibroblast-enriched histone methyltransferase Dot1L prevents cardiac fibrosis and cardiac dysfunction Cell & Bioscience Dot1L Cardiac Fibrosis Cardiac fibroblasts Cardiac function FoxO3a |
| title | Inhibition of the cardiac fibroblast-enriched histone methyltransferase Dot1L prevents cardiac fibrosis and cardiac dysfunction |
| title_full | Inhibition of the cardiac fibroblast-enriched histone methyltransferase Dot1L prevents cardiac fibrosis and cardiac dysfunction |
| title_fullStr | Inhibition of the cardiac fibroblast-enriched histone methyltransferase Dot1L prevents cardiac fibrosis and cardiac dysfunction |
| title_full_unstemmed | Inhibition of the cardiac fibroblast-enriched histone methyltransferase Dot1L prevents cardiac fibrosis and cardiac dysfunction |
| title_short | Inhibition of the cardiac fibroblast-enriched histone methyltransferase Dot1L prevents cardiac fibrosis and cardiac dysfunction |
| title_sort | inhibition of the cardiac fibroblast enriched histone methyltransferase dot1l prevents cardiac fibrosis and cardiac dysfunction |
| topic | Dot1L Cardiac Fibrosis Cardiac fibroblasts Cardiac function FoxO3a |
| url | https://doi.org/10.1186/s13578-022-00877-5 |
| work_keys_str_mv | AT jiexu inhibitionofthecardiacfibroblastenrichedhistonemethyltransferasedot1lpreventscardiacfibrosisandcardiacdysfunction AT jinghuanwang inhibitionofthecardiacfibroblastenrichedhistonemethyltransferasedot1lpreventscardiacfibrosisandcardiacdysfunction AT fenlong inhibitionofthecardiacfibroblastenrichedhistonemethyltransferasedot1lpreventscardiacfibrosisandcardiacdysfunction AT wenzhong inhibitionofthecardiacfibroblastenrichedhistonemethyltransferasedot1lpreventscardiacfibrosisandcardiacdysfunction AT haibisu inhibitionofthecardiacfibroblastenrichedhistonemethyltransferasedot1lpreventscardiacfibrosisandcardiacdysfunction AT zhenghuasu inhibitionofthecardiacfibroblastenrichedhistonemethyltransferasedot1lpreventscardiacfibrosisandcardiacdysfunction AT xinhualiu inhibitionofthecardiacfibroblastenrichedhistonemethyltransferasedot1lpreventscardiacfibrosisandcardiacdysfunction |