Global methylome analysis and histidine methylation analysis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Mingliang Ye
PROVIDER: PXD047739 | iProX | Tue Dec 12 00:00:00 GMT 2023
REPOSITORIES: iProX
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Project description:We here describe our independent uncovering of CARNMT1 as a protein histidine methyltransferase (HMT), and our extensive efforts on defining its substrate specificity and methylation targets. We found that recombinant CARNMT1 methylated MYLK2-derived peptide containing His-148 in vitro. The recombinant CARNMT1 methylated also several proteins in extracts from CARNMT1 KO cells, and, using protein mass spectrometry, we identified several fully methylated CARNMT1 targets, all of which were C3H zinc finger (C3H ZnF) proteins. These included the previously identified U2AF1, ZC3H15 and ZC3H18, but also the novel substrates RBM22, PPP1R10, PRR3 and RNF113A. We also identified several of the homologous methylation events in Caenorhabditis elegans and showed that they could be introduced by the nematode CARNMT in vitro.
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Project description:Protein arginine methylation, catalyzed by the protein arginine methyltransferase (PRMT) family, is recognized as a widespread post-translational modification (PTM) with implications in a plethora of biological processes in eukaryotes. PRMT proteins were classified into three types, type I, II and III, according to the final methyl-arginine products generated. Despite that thousands of substrates have been identified for Type I and II PRMTs, a full scope of arginine methylation catalyzed by the only type III PRMT, PRMT7, as well as its connection with that of type I and II PRMTs remain unknown, limiting our understanding of the network of arginine methylation and its functions in cells. In this study, global profiling of PRMT4 (type I), PRMT5 (type II) and PRMT7 (type III) substrates (also referred as methylome) revealed that PRMT7 methylated a GAR (glycine and arginine) motif similar as PRMT5, while PRMT4 uniquely methylated a motif in which proline was highly enriched. PRMT4, 5 and 7-methylome were all enriched with proteins functioning in mRNA splicing.
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Project description:S-adenosylmethionine (SAM) is the principal biological methyl group donor for a diverse range of substrates. It is synthesised in the cytosolic methionine cycle and shuttled throughout the cell. The mitochondrial SAM (mitoSAM) pool depends on import through the inner-membrane S-adenosylmethionine carrier (SAMC) and supports the maturation of metabolites and mitochondrial RNAs. Mutations in SAMC in patients cause a severe metabolic crisis, however, the organellar regulation of mitoSAM and the protein methylation landscape within mitochondria are largely unknown. We developed a fly-compatible SILAC labelling technique and mapped mitochondrial protein methylation sites in Drosophila melanogaster, further showing that SAM is the sole methyl group donor for these modifications, with no contribution from folate-species. This dataset comprises MS-runs used for quality control of methyl-SILAF, the methylome mapping and exclusion of folates as protein methyl-group donors.
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Project description:We used Methyl-MiniSeq platform from Zymo Research company to identify genome-wide methylation changes affected by lncRNA H19 knockdown in myotubes. Following H19 knockdown, we observed extensive genome-wide mthylation pattern changes relative to siCon cells, with some genes showing incresed methylation, others showing decreased methylation, and a third group with no significant change. Myotubes differentiated from mouse C3H myoblasts were transfected with either control siRNA or siH19, 48h later, cellular genomic DNA was extracted and subjected to genome-scale DNA methylation mapping using the platform of an improved version of Reduced Representation Bisulfite Sequencing (RRBS).
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Project description:Elevated plasma homocysteine is an independent risk factor for cardiovascular disease and stroke, however the etiology remains poorly understood. Elevated homocysteine is known to inhibit methyltransferases including DNA methyltransferases, but no methylome-wide analysis of elevated homocysteine has been reported. Peripheral blood genomic DNA methylation in 8 Singaporean-Chinese ischemic stroke patients (4 male, 4 female) with varying homocysteine titer and hypertensive status were profiled using methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq) on Illumina Genome Analyzer IIx. A methylome wide screen was undertaken for gender, total plasma homocysteine, hypertension and age. The data show considerable variability within the small cohort, including at genes which are related to one carbon metabolism and cardiovascular disease. Peripheral blood genomic DNA methylation in 8 Singaporean-Chinese ischemic stroke patients (4 male, 4 female) was profiled using methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq) on Illumina Genome Analyzer IIx. Methylation parrterns were correlated with homocysteine levels, lypertensive status, gender and age.
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Project description:In addition to predominant protein methylation on lysine and arginine residues, histidine also serves as a substrate for the modification. However, a limited number of enzymes responsible for this modification has been reported. Moreover, the biological mission of the histidine methylation has remained poorly understood. Here, we reported that human METTL18 is a histidine methyltransferase for ribosomal protein RPL3 and that the modification specifically slows ribosome traverse on tyrosine codons, allowing proper folding of synthesized proteins. Harnessing in vitro methylation assay with methyl-donor analogue and quantitative mass spectrometry, we identified that His245 of RPL3 is methylated at τ-N position by METTL18. Structural comparison of the modified and unmodified ribosomes showed the stoichiometric modification and suggested its role in translation tuning. Indeed, genome-wide ribosome profiling revealed the suppressed ribosomal translocation at tyrosine codons by RPL3 methylation. Because the slower elongation provides enough time for nascent protein folding, RPL3 methylation protects cells from cellular aggregation of Tyr-rich proteins. Our results reveal histidine methylation as an example of “ribosome code”, which ensures proteome integrity in cells.
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Project description:Protein methylation occurs predominantly on lysine and arginine residues, but histidine also serves as a substrate for the modification. However, a limited number of enzymes responsible for this modification have been reported. Moreover, the biological role of histidine methylation has remained poorly understood. Here, we report that human METTL18 is a histidine methyltransferase for the ribosomal protein RPL3 and that the modification specifically slows ribosome traverse on tyrosine codons, allowing the proper folding of synthesized proteins. By performing an in vitro methylation assay with a methyl donor analog and quantitative mass spectrometry, we found that His245 of RPL3 is methylated at the τ-N position by METTL18. Structural comparison of the modified and unmodified ribosomes showed stoichiometric modification and suggested a role in translation tuning. Indeed, genome-wide ribosome profiling revealed suppressed ribosomal translocation at tyrosine codons by RPL3 methylation. Because the slower elongation provides enough time for nascent protein folding, RPL3 methylation protects cells from the cellular aggregation of Tyr-rich proteins. Our results reveal histidine methylation as an example of a “ribosome code” that ensures proteome integrity in cells.
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Project description:The Oxford Nanopore technology has a great potential for the analysis of genome methylation, including full-genome methylome profiling. However, there are certain issues while identifying methylation motif sequences caused by low sensitivity of the currently available motif enrichment algorithms. Here, we present Snapper, a new highly-sensitive approach to extract methylation motif sequences based on a greedy motif selection algorithm. Snapper has shown higher enrichment sensitivity compared with the MEME tool coupled with Tombo or Nanodisco instruments, which was demonstrated on H. pylori strain J99 studied earlier using the PacBio technology. In addition, we used Snapper to characterize the total methylome of a new H.pylori strain A45. The analysis revealed the presence of at least 4 methylation sites that have not been described for H. pylori earlier. We experimentally confirmed a new CCAG-specific methyltransferase and indirectly inferred a new CCAAK-specific methyltransferase.
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