RRC ID 79152
Author Katanasaka Y, Yabe H, Murata N, Sobukawa M, Sugiyama Y, Sato H, Honda H, Sunagawa Y, Funamoto M, Shimizu S, Shimizu K, Hamabe-Horiike T, Hawke P, Komiyama M, Mori K, Hasegawa K, Morimoto T.
Title Fibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice.
Journal Nat Commun
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.
Volume 15(1)
Pages 2472
Published 2024-3-19
DOI 10.1038/s41467-024-46711-z
PII 10.1038/s41467-024-46711-z
PMID 38503742
PMC PMC10951424
MeSH Animals Fibroblasts* / metabolism Fibrosis Heart Male Mice Protein-Arginine N-Methyltransferases / genetics Protein-Arginine N-Methyltransferases / metabolism Transforming Growth Factor beta / metabolism Ventricular Dysfunction, Left* / genetics
DNA material pCMFlag_hsSMAD3 (RDB07019)