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Transcriptome analysis of CARNMT1 knockout tissue

ABSTRACT: Histidine (His) residues are methylated in various proteins, but their roles and regulation mechanisms remain unknown. Here, we showed that CARNMT1, a known His methyltransferase of dipeptide carnosine (βAla-His), is the major protein His N-position-specific methyltransferase. ProSeAM labeling and proteomic analysis revealed that 52 His sites in 20 proteins underwent CARNMT1-mediated methylation. The consensus methylation site for CARNMT1 was identified as Cx(F/Y)xH, which is a C3H zinc finger (C3H-ZF) motif. CARNMT1-deficient and catalytically-inactive mutant mice showed embryonic lethality. Among the CARNMT1-target C3H-ZF proteins, RNA degradation mediated by Roquin and TTP was affected by CARNMT1 and its enzymatic activity. Furthermore, splicing factor, U2AF1’s 3’-splice site recognition was perturbed and pre-mRNA alternative splicing (AS) was also affected by CARNMT1 deficiency. These findings indicate that CARNMT1-mediated protein His methylation, which is essential for embryogenesis, plays roles in diverse aspects of RNA metabolism by targeting C3H-ZF-type RNA-binding proteins and modulating their functions, including pre-mRNA AS and regulation of mRNA degradation.

ORGANISM(S): Mus musculus

PROVIDER: GSE228894 | GEO | 2023/09/06

REPOSITORIES: GEO

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The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes

Project description:Post-translational methylation plays a crucial role in regulating and optimizing protein function. Protein histidine methylation, occurring as the two isomers 1- and 3- methylhistidine (1MH and 3MH), was first reported five decades ago, but remains largely unexplored. Here we report that METTL9 is a broad-specificity methyltransferase (MTase) that mediates the formation of the majority of 1MH present in mouse and human proteomes. The minimal requirement for METTL9-catalyzed methylation is a His-x-His (HxH) motif, where "x" is preferably a small amino acid, allowing METTL9 to methylate a number of HxH-containing proteins. Here, we show that the immunomodulatory protein S100A9 and the NDUFB3 subunit of mitochondrial respiratory Complex I are methylated at HxH motif using MALDI-TOF MS.

2020-11-23 | PXD022067 | Pride

Non-CG methylation patterns shape the epigenetic landscape in Arabidopsis

Project description:DNA methylation occurs in both CG and non-CG sequence contexts. Non-CG methylation is abundant in plants, and is mediated by CHROMOMETHYLASE (CMT) and DOMAINS REARRANGED METHYLTRANSFERASE (DRM) proteins; however its roles remain poorly understood. Here we characterize the roles of non-CG methylation in Arabidopsis thaliana. We show that a poorly characterized methyltransferase, CMT2, is a functional methyltransferase in vitro and in vivo. CMT2 specifically binds histone H3 lysine 9 (H3K9) dimethylation and methylates non-CG cytosines at sites that are also regulated by H3K9 dimethylation. By generating different combinations of non-CG methylation mutants, we reveal the contributions and redundancies between each methyltransferase in DNA methylation patterning and in regulating transposable elements (TEs) and protein-coding genes. We also demonstrate extensive dependencies of small RNA accumulation and H3K9 methylation patterning on non-CG methylation, suggesting self-reinforcing mechanisms between these epigenetic factors. The results suggest that non-CG methylation patterns are critical in shaping the histone modification and small non-coding RNA landscapes. Eighteen mRNA-seq samples, five smRNA-seq samples, five bisulfite-seq samples, twenty ChIP-seq samples. Bisulfite-seq data for cmt2-7 single mutants, cmt3 single mutants, drm1/2 double mutants, drm1/2 cmt3 triple mutants are deposited in GSE39901. Processed wiggle format files for all datasets can be downloaded at http://genomes.mcdb.ucla.edu/AthBSseq/

2013-12-15 | E-GEOD-51304 | biostudies-arrayexpress

Gene expression profile in Caco-2 cells treated with carnosine

Project description:To reveal the effects of carnosine on Caco-2 cells, we have employed whole genome microarray to detect genes that showed significantly different expression when exposed to carnosine. Caco-2 cells were treated with 1 mM carnosine for 3 days. Caco-2 cells were treated with 1 mM carnosine for 3 days. Three independent experiments were performed.

2015-03-31 | E-GEOD-61455 | biostudies-arrayexpress

Arabidopsis Messenger RNA N6-methyladenosine Demethylation Regulates Plant Development

Project description:N6-methyladenosine (m6A) is the most abundant internal modification in the messenger RNA (mRNA) of all higher eukaryotes. This modification has been shown to be reversible in mammals; it is installed by a methyltransferase heterodimer complex of METTL3 and METTL14 bound with WTAP, and reversed by iron(II)- and Î±-ketoglutarate-dependent demethylases FTO and ALKBH5. This modification exhibits significant functional roles in various biological processes. The m6A modification as a RNA mark is recognized by reader proteins, such as YTH domain family proteins and HNRNPA2B1; m6A can also act as a structure switch to affect RNA-protein interactions for biological regulation. In Arabidopsis thaliana, the methyltransferase subunit MTA (the plant orthologue of human METTL3, encoded by At4g10760) was well characterized and FIP37 (the plant orthologue of human WTAP) was first identified as the interacting partner of MTA. Here we report the discovery and characterization of reversible m6A methylation mediated by AtALKBH10B (encoded by At4g02940) in A. thaliana, and noticeable roles of this RNA demethylase in affecting plant development and floral transition. Our findings reveal potential broad functions of reversible mRNA methylation in plants. m6A peaks were identified from wild type Columbia-0 and atalkbh10b-1 mutant in two biological replicates

2016-03-24 | E-GEOD-79523 | biostudies-arrayexpress

Proteomic Analysis of Protein Methylation in the Yeast Saccharomyces cerevisiae

Project description:Protein methylation catalyzed by SAM-dependent methyltransferase represents a major PTM involved in important biological processes. Because methylation can occur on nitrogen, oxygen and sulfur centers and multiple methylation states exist on the nitrogen centers, methylproteome remains poorly documented. Here we present the methylation by isotope labeled SAM (MILS) strategy for a highly-confident analysis of the methylproteome of the SAM-auxotrophic Saccharomyces cerevisiae based on the online multidimensional μHPLC/MS/MS technology. We identified 117 methylated proteins, containing 182 methylation events associated with 174 methylation sites. About 90% of these methylation events were previously unknown. Our results indicated, 1) over 6% of the yeast proteome are methylated, 2) the amino acid residue preference of protein methylation follows the order Lys >> Arg > Asp > Glu ≈ Gln ≈ Asp > His > Cys, 3) the methylation state on nitrogen center is largely exclusive, and 4) the methylated proteins are located mainly in nucleus/ribosome associated with translation/transcription and DNA/RNA processing. Our dataset is the most comprehensive methylproteome known-to-date of all living organisms, and should significantly contribute to the field of protein methylation and related research.

2020-01-27 | PXD000606 | Pride

Genomic deletion by CRISPR/Cas9 reveals a critical role for Evx1as/Evx1 locus in regulating embryonic stem cell differentiation

Project description:We report that head to head long noncoding RNAs contribute to transcription and developmental process. Thousands of lncRNAs have been identified in the whole genome, and classified to several subgroups based on the genome position with their coding neighbors. XH, the head to head subgroup is associated with transcription and development in GO analysis. Here, we deleted the promoter and exon1 region which shared by Evx1as/Evx1 XH pair in embryonic stem cells by two sgRNAs-mediated CRISPR. Two homozygous mutants came out from 46 single clones with high efficiency, while two control clones were picked from cells which were only Cas9 transfected. These two mutants failed to activate Evx1 in -LIF differentiation compared to control cells, while Evx1as still have 30% mRNA residual. Meanwhile, we characterized gene expression level among different stages of ESC differentiation and found many differentiated related makers exhibited aberrant regulation, especially endodermal genes. We propose that XH lncRNA and its coding neighbor could regulate each other, and function as a unit to promote ESC differentiation and biological development.

2016-03-24 | GSE58801 | GEO

Gene expression profile in Caco-2 cells treated with carnosine

2015-03-31 | GSE61455 | GEO

Iron scavenging and suppression of collagen cross-linking underlie antifibrotic effects of carnosine in the heart with obesity

Project description:Oral consumption of histidyl dipeptides such as l-carnosine has been suggested to promote cardiometabolic health, although therapeutic mechanisms remain incompletely understood. We recently reported that oral consumption of a carnosine analog suppressed markers of fibrosis in liver of obese mice, but whether antifibrotic effects of carnosine extend to the heart is not known, nor are the mechanisms by which carnosine is acting. Here, we investigated whether oral carnosine was able to mitigate the adverse cardiac remodeling associated with diet induced obesity in a mouse model of enhanced lipid peroxidation (i.e., glutathione peroxidase 4 deficient mice, GPx4+/−), a model which mimics many of the pathophysiological aspects of metabolic syndrome and T2 diabetes in humans. Wild-type (WT) and GPx4+/− male mice were randomly fed a standard (CNTL) or high fat high sucrose diet (HFHS) for 16 weeks. Seven weeks after starting the diet, a subset of the HFHS mice received carnosine (80 mM) in their drinking water for duration of the study. Carnosine treatment led to a moderate improvement in glycemic control in WT and GPx4+/− mice on HFHS diet, although insulin sensitivity was largely unchanged. Interestingly, while our transcriptomic analysis revealed that carnosine therapy had no significant impact on global gene expression in the heart, carnosine substantially upregulated cardiac GPx4 expression in both WT and GPx4+/− mice on HFHS diet. Carnosine also significantly reduced protein carbonyls and iron levels in myocardial tissue from both genotypes on HFHS diet. Importantly, we observed a robust antifibrotic effect of carnosine therapy in hearts from mice on HFHS diet, which further in vitro experiments suggest is due to carnosine’s ability to suppress collagen-cross-linking. Collectively, this study reveals antifibrotic potential of carnosine in the heart with obesity and illustrates key mechanisms by which it may be acting.

2023-12-19 | GSE250315 | GEO

RNA-Sequencing of carnosine treated wild-type BDF1 (WT) and transgenic Thy1-aSyn mice

Project description:Mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease (PD). This study tested the hypothesis that the dipeptide carnosine would exert a beneficial effect in the Thy1-aSyn mouse model of PD, which displays mitochondrial dysfunction. Mitochondrial function and gene expression were evaluated in the midbrain after two months of carnosine administration by intranasal (IN) or drinking water routes of exposure. IN carnosine attenuated transcriptional changes in the midbrain in Thy1-aSyn mice. Additionally, IN-carnosine increased expression of mitochondria complexes and enhanced mitochondrial function, suggesting a potential neuroprotective role for IN-carnosine in PD.

2018-12-31 | GSE115769 | GEO

Location and Function of Cytosine-5 Methylation in RNA

Project description:Mutations in the cytosine-5 RNA methyltransferase NSun2 can cause neurodevelopmental disorders and symptoms commonly found in patients with Dubowitz-like syndrome. Some tRNAs are known to be methylated NSun2, however the occurrence of cytosine-5 methylation (m5C) in other RNA biotypes is still under debate. Location in RNA and function of m5C has not been studied yet. This study is aimed at identifying new m5C methylated RNA biotypes, as well as the location at specific structures or sequences and the ultimate biological function. The impact of the loss of NSun2-mediated methylation is also determined by comparing gene expression data with the global cytosine-5 RNA methylome in Dubowitz-like syndrome patients. We also use ribosomal profiling to assess the impact of the loss and rescue of Nsun2-mediated cytosine-5 RNA methylation on translation rates and ribosome occupancy.

| phs000645 | dbGaP

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