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.
Arabidopsis floral initiator SKB1 confers high salt tolerance by regulating transcription and pre-mRNA splicing through altering histone H4R3 and small nuclear ribonucleoprotein LSM4 methylation
Plants adapt their growth and development in response to perceived salt stress. Although DELLA-dependent growth restraint is thought to be an integration of the plant’s response to salt stress, little is known about how histone modification confers salt stress and, in turn, affects development.
Here, we report that floral initiator Shk1 kinase binding protein1 (SKB1) and histone4 arginine3 (H4R3) symmetric dimethylation (H4R3sme2) integrate responses to plant developmental progress and salt stress.
Mutation of SKB1 results in salt hypersensitivity, late flowering, and growth retardation. SKB1 associates with chromatin and thereby increases the H4R3sme2 level to suppress the transcription of FLOWERING LOCUS C (FLC) and a number of stress-responsive genes.
During salt stress, the H4R3sme2 level is reduced, as a consequence of SKB1 disassociating from chromatin to induce the expression of FLC and the stress-responsive genes but increasing the methylation of small nuclear ribonucleoprotein Sm-like4 (LSM4).
Splicing defects are observed in the skb1 and lsm4 mutants, which are sensitive to salt. We propose that SKB1 mediates plant development and the salt response by altering the methylation status of H4R3sme2 and LSM4 and linking transcription to pre-mRNA splicing.
H4R3 methylation facilitates beta-globin transcription by regulating histone acetyltransferase binding and H3 acetylation
Histone modifications play an important role in the process o1f transcription. However, in contrast to lysine methylation, the role of arginine methylation in chromatin structure and transcription has been underexplored.
The globin genes are regulated by a highly organized chromatin structure that juxtaposes the locus control region (LCR) with downstream globin genes.
We report here that the targeted recruitment of asymmetric dimethyl H4R3 catalyzed by PRMT1 (protein arginine methyltransferase 1) facilitates histone H3 acetylation on Lys9/Lys14.
Dimethyl H4R3 provides a binding surface for P300/CBP-associated factor (PCAF) and directly enhances histone H3 acetylation in vitro.
We show that these active modifications are essential for efficient interactions between the LCR and the beta(maj)-promoter as well as transcription of the beta-globin gene.
Furthermore, knockdown (KD) of PRMT1 by RNA interference in erythroid progenitor cells prevents histone acetylation, enhancer and promoter interaction, and recruitment of transcription complexes to the active beta-globin promoter.
Reintroducing rat PRMT1 into the PRMT1 KD MEL cells rescues PRMT1 binding, beta-globin transcription, and erythroid differentiation.
Taken together, our data suggest that PRMT1-mediated dimethyl H4R3 facilitates histone acetylation and enhancer/promoter communications, which lead to the efficient recruitment of transcription preinitiation complexes to active promoters.
PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing.
Mammalian gene silencing is established through methylation of histones and DNA, although the order in which these modifications occur remains contentious.
Using the human beta-globin locus as a model, we demonstrate that symmetric methylation of histone H4 arginine 3 (H4R3me2s) by the protein arginine methyltransferase PRMT5 is required for subsequent DNA methylation. H4R3me2s serves as a direct binding target for the DNA methyltransferase DNMT3A, which interacts through the ADD domain containing the PHD motif.
Loss of the H4R3me2s mark through short hairpin RNA-mediated knockdown of PRMT5 leads to reduced DNMT3A binding, loss of DNA methylation and gene activation.
In primary erythroid progenitors from adult bone marrow, H4R3me2s marks the inactive methylated globin genes coincident with localization of PRMT5.
Our findings define DNMT3A as both a reader and a writer of repressive epigenetic marks, thereby directly linking histone and DNA methylation in gene silencing.
Histone demethylase IBM1-mediated meiocyte gene expression ensures meiotic chromosome synapsis and recombination
Histone methylation and demethylation play important roles in plant growth and development, but the involvement of histone demethylation during meiosis is poorly understood.
Here we show that disruption of Arabidopsis thaliana INCREASE IN BONSAI METHYLATION 1 (IBM1) causes incomplete synapsis, chromosome entanglement and reduction of recombination during meiosis, leading to sterility.
Interestingly, these ibm1 meiotic defects are rescued by mutations in either SUVH4/KYP or CMT3. Using transcriptomic analyses we show that mutation of IBM1 down-regulates thousands of genes expressed in meiocytes, and that expression of about 38% of these genes are restored to wild type levels in ibm1 cmt3 double mutants.
Histone H4R3 Methylation Antibody Panel Pack |
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| C10019 | EpiGentek |
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Histone H3R17 Methylation Antibody Panel Pack |
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| C10017 | EpiGentek |
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Histone H3R26 Methylation Antibody Panel Pack |
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| C10018 | EpiGentek |
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Histone H3R2 Methylation Antibody Panel Pack |
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| C10015 | EpiGentek |
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Histone H3R8 Methylation Antibody Panel Pack |
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| C10016 | EpiGentek |
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Histone H3K4 Methylation Antibody Panel Pack |
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| C10005 | EpiGentek |
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Histone H3K9 Methylation Antibody Panel Pack |
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| C10006 | EpiGentek |
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Histone H3K27 Methylation Antibody Panel Pack |
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| C10007 | EpiGentek |
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Histone H3K36 Methylation Antibody Panel Pack |
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| C10008 | EpiGentek |
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Histone H3K79 Methylation Antibody Panel Pack |
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| C10009 | EpiGentek |
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Changes in the expression of 437 of these, including the ARABIDOPSIS MEI2-LIKE AML3-5 genes, are correlated with a significant reduction of gene body CHG methylation.
Consistently, the aml3 aml4 aml5 triple has defects in synapsis and chromosome entanglement similar to ibm1. Genetic analysis shows that aml3 aml4 aml5 ibm1 quadruple mutants resemble the ibm1 single mutant.
Strikingly, overexpression of AML5 in ibm1 can partially rescue the ibm1 meiotic defects.
Taken together, our results demonstrate that histone demethylase IBM1 is required for meiosis likely via coordinated regulation of meiocyte gene expression during meiosis.