Histone H4R3 symmetric di-methylation by Prmt5 protects against cardiac hypertrophy via regulation of Filip1L/β-catenin

Background and purpose: Although histone lysine methylation has been extensively studied for their participation in pathological cardiac hypertrophy, the potential regulatory role of histone arginine methylation remains to be elucidated. The present study focused on H4R3 symmetric di-methylation (H4R3me2s) induced by protein arginine methyltransferase 5 (Prmt5), and explored its epigenetic regulation and underlying mechanisms in cardiomyocyte hypertrophy.
Methods and results: 1. The expressions of Prmt5 and H4R3me2s were suppressed in cardiac hypertrophy models in vivo and in vitro; 2. Prmt5 silencing or its inhibitor EPZ, or knockdown of cooperator of Prmt5 (Copr5) to disrupt H4R3me2s, facilitated cardiomyocyte hypertrophy, whereas overexpression of wild type Prmt5 rather than the inactive mutant protected cardiomyocytes against hypertrophy; 3.
The chIP-sequence analysis identified Filip1L as a target gene of Prmt5-induced H4R3me2s; 4. Knockdown or inhibition of Prmt5 impaired Filip1L transcription and subsequently prevented β-catenin degradation, thus augmenting cardiomyocyte hypertrophy.
Conclusions: the present study reveals that Prmt5-induced H4R3me2s ameliorates cardiomyocyte hypertrophy by transcriptional upregulation of Filip1L and subsequent enhancement of β-catenin degradation.
Deficiency of Prmt5 and the resulting suppression of H4R3me2s might facilitate the development of pathological cardiac hypertrophy.
Prmt5 might serve as a key epigenetic regulator in pathological cardiac hypertrophy.
Keywords: EPZ (PubChem CID: 90241673); Filip1L; H4R3me2s; Isoproterenol hydrochloride (PubChem CID: 5807); Pathological cardiac hypertrophy; Prmt5; β-catenin.

Histone H4R3 methylation catalyzed by SKB1/PRMT5 is required for maintaining shoot apical meristem.

The shoot apical meristem (SAM) is the source of all of the above-ground tissues and organs in post-embryonic development in higher plants. Studies have proven that the expression of genes constituting the WUSCHEL (WUS)-CLAVATA (CLV) feedback loop is critical for SAM maintenance. Several histone lysine acetylations and methylation markers have been proven to regulate the transcription level of WUS.
However, little is known about how histone arginine methylation regulates the expression of WUS and other genes. Here, we report that H4R3 symmetric dimethylation (H4R3sme2) mediated by SKB1/PRMT5 represses the expression of CORYNE (CRN) to maintain normal SAM geometrics. SKB1 lesion results in small SAM size in Arabidopsis, as well as down-regulated expression of WUS and CLV3.
Up-regulation of WUS expression enlarges SAM size in skb1 mutant plants. We find that SKB1 and H4R3sme2 associate with the chromatin of the CRN locus to down-regulate its transcription.
Mutation of CRN rescues the expression of WUS and the small SAM size of skb1. Thus, SKB1 and SKB1-mediated H4R3sme2 are required for the maintenance of SAM in Arabidopsis seedlings.

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