| Autor: |
Yasufumi Katanasaka, Harumi Yabe, Noriyuki Murata, Minori Sobukawa, Yuga Sugiyama, Hikaru Sato, Hiroki Honda, Yoichi Sunagawa, Masafumi Funamoto, Satoshi Shimizu, Kana Shimizu, Toshihide Hamabe-Horiike, Philip Hawke, Maki Komiyama, Kiyoshi Mori, Koji Hasegawa, Tatsuya Morimoto |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-13 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-46711-z |
| Popis: |
Abstract Protein arginine methyltransferase 5 (PRMT5) is a well-known epigenetic regulatory enzyme. However, the role of PRMT5-mediated arginine methylation in gene transcription related to cardiac fibrosis is unknown. Here we show that fibroblast-specific deletion of PRMT5 significantly reduces pressure overload-induced cardiac fibrosis and improves cardiac dysfunction in male mice. Both the PRMT5-selective inhibitor EPZ015666 and knockdown of PRMT5 suppress α-smooth muscle actin (α-SMA) expression induced by transforming growth factor-β (TGF-β) in cultured cardiac fibroblasts. TGF-β stimulation promotes the recruitment of the PRMT5/Smad3 complex to the promoter site of α-SMA. It also increases PRMT5-mediated H3R2 symmetric dimethylation, and this increase is inhibited by Smad3 knockdown. TGF-β stimulation increases H3K4 tri-methylation mediated by the WDR5/MLL1 methyltransferase complex, which recognizes H3R2 dimethylation. Finally, treatment with EPZ015666 significantly improves pressure overload-induced cardiac fibrosis and dysfunction. These findings suggest that PRMT5 regulates TGF-β/Smad3-dependent fibrotic gene transcription, possibly through histone methylation crosstalk, and plays a critical role in cardiac fibrosis and dysfunction. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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Full text from SpringerLink