Integrated multilayer omics reveals the genomic, proteomic and metabolic influences of the histidyl dipeptides on heart
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE192583 | GEO | 2021/12/27
REPOSITORIES: GEO
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Project description:Histidyl dipeptides, such as carnosine, present in a micro-millimolar ranges in the heart, are synthesized via the enzyme carnosine synthase (Carns). These dipeptides facilitate glycolysis by proton buffering, form conjugates with reactive aldehydes, such as acrolein, and attenuate ischemia and reperfusion injury. While these dipeptides exhibit multifunctional properties, a composite understanding of their roles in myocardium is lacking. To identify the landscape of histidyl dipeptide mediated responses in the heart, we used a triomics approach of genome wide RNA sequencing, global proteomics and unbiased metabolomics in the cardio specific Carns transgenic (Tg) mice and integrated the three data sets.
2021-12-25 | PXD030647 |
Project description:Histidyl dipeptides, such as carnosine, present in a micro-millimolar ranges in the heart, are synthesized via the enzyme carnosine synthase (Carns). These dipeptides facilitate glycolysis by proton buffering, form conjugates with reactive aldehydes, such as acrolein, and attenuate ischemia and reperfusion injury. While these dipeptides exhibit multifunctional properties, a composite understanding of their roles in myocardium is lacking. To identify the landscape of histidyl dipeptide mediated responses in the heart, we used a triomics approach of genome wide RNA sequencing, global proteomics and unbiased metabolomics in the cardio specific Carns transgenic (Tg) mice and integrated the three data sets. Our result show higher myocardial levels of histidyl dipeptides lead to extensive changes in several microRNAs, which could target the expression of contractile proteins, beta-fatty acid oxidation and citric acid cycle (TCA) enzymes. Global proteomics shows, expression of contractile proteins, enzymes of beta-fatty acid oxidation and TCA cycle, were enriched in the CarnsTg heart. Under aerobic conditions, the CarnsTg hearts had lower levels of short and long-chain fatty acids and TCA cycle intermediate-succinic acid, whereas, under ischemic conditions the accumulation of fatty acids and TCA cycle intermediates were significantly attenuated in the CarnsTg heart. Integration of multiple data sets suggests that beta-fatty acid oxidation and TCA cycle pathways exhibited correlative changes in the CarnsTg hearts at all three levels. Our triomics approach shows histidyl dipeptides are critical regulators of myocardial structure, function and energetics.
2021-12-15 | ST002056 | MetabolomicsWorkbench
Project description:Integrated multilayer omics reveals the genomic, proteomic and metabolic influences of the histidyl dipeptides on heart
| PRJNA792134 | ENA
Project description:Background Histidyl dipeptides such as carnosine are present in a micromolar to millimolar range in mammalian hearts. These dipeptides facilitate glycolysis by proton buffering. They form conjugates with reactive aldehydes, such as acrolein, and attenuate myocardial ischemia-reperfusion injury. Although these dipeptides exhibit multifunctional properties, a composite understanding of their role in the myocardium is lacking. Methods and Results To identify histidyl dipeptide-mediated responses in the heart, we used an integrated triomics approach, which involved genome-wide RNA sequencing, global proteomics, and unbiased metabolomics to identify the effects of cardiospecific transgenic overexpression of the carnosine synthesizing enzyme, carnosine synthase (Carns), in mice. Our result showed that higher myocardial levels of histidyl dipeptides were associated with extensive changes in the levels of several microRNAs, which target the expression of contractile proteins, β-fatty acid oxidation, and citric acid cycle (TCA) enzymes. Global proteomic analysis showed enrichment in the expression of contractile proteins, enzymes of β-fatty acid oxidation, and the TCA in the Carns transgenic heart. Under aerobic conditions, the Carns transgenic hearts had lower levels of short- and long-chain fatty acids as well as the TCA intermediate-succinic acid; whereas, under ischemic conditions, the accumulation of fatty acids and TCA intermediates was significantly attenuated. Integration of multiple data sets suggested that β-fatty acid oxidation and TCA pathways exhibit correlative changes in the Carns transgenic hearts at all 3 levels. Conclusions Taken together, these findings reveal a central role of histidyl dipeptides in coordinated regulation of myocardial structure, function, and energetics.
| S-EPMC9333374 | biostudies-literature
Project description:Human umbilical vein endothelial cells (HUVECs) are a widely-used model system to study pathological and physiological processes associated with the cardiovascular system. An understanding of genes and proteins that are expressed in any cell type is a fundamental need which facilitates studies of molecular changes in disease states and response to various stimuli. In this study, we employed next generation sequencing and mass spectrometry to profile the transcriptome and proteome of primary HUVECs. Analysis of 145 million paired-end reads from next generation sequencing confirmed expression of 12,186 protein-coding genes (FPKM>0.1), 439 novel long non-coding RNAs and revealed 6,089 novel isoforms that were not annotated in GENCODE. A comparison of the transcripts against human gene expression data for 53 tissues catalogued by the Genotype-Tissue Expression (GTEx) project revealed a number of HUVEC-specific genes. Proteomics analysis identified 6,477 proteins including confirmation of N-termini for 1,091 proteins and isoforms for 149 proteins for which transcriptomic evidence was observed. Alternate translational start sites for seven proteins and alternate splicing in five proteins were also identified. A database search to specifically identify other post-translational modifications provided evidence for a number of modification sites on 117 proteins which included ubiquitylation, lysine acetylation and mono, di- and tri-methylation events. Based on the data from this study and a survey of other databases, we provide evidence for 11 “missing proteins,” which are proteins for which there was insufficient or no protein level evidence. Peptides supporting missing protein and novel events were validated by comparison of MS/MS fragmentation patterns with synthetic peptides. By creating a custom database of proteins containing sample-specific single amino acid variants (SAAV), we also identified 245 variant peptides derived from 207 expressed proteins. Overall, we believe that the integrated approach employed in this study is widely applicable to study any primary cell type for deeper molecular characterization.
2019-10-28 | GSE115536 | GEO
Project description:Metabolic adaption to different host niches is one of the most important virulence traits of human fungal pathogens. The metabolic versatility of fungi and other cellular processes such as proliferation, morphogenesis and stress responses are tightly regulated by complex networks in which protein kinases play a crucial role. Serine-arginine (SR) protein kinases are highly conserved in all eukaryotes, but their function in pathogenic Candida spp. has not yet been investigated. C. albicans genome encodes two (Sky1, Sky2) and Candida glabrata one (Sky1) homolog of the human SR protein kinase 1 (SRPK1). We utilized deletion strains of the respective genes in both fungi in order to examine their cellular functions. C. glabrata and C. albicans strains lacking SKY1 exhibited higher resistance to osmotic stress and toxic polyamine concentrations to their ortholog in the model yeast Saccharomyces cerevisiae Sky1. Deletion of SKY2 in C. albicans resulted in impaired utilization of dipeptides as the sole nitrogen source. Subsequent phosphoproteomic analysis identified Ptr22, a transporter of di- and tri-peptides in C. albicans, as a potential Sky2 substrate. Overexpression of PTR22 in the sky2∆ restored the ability to grow on dipeptides as the sole nitrogen source and rendered the cells more susceptible to the dipeptide antibiotics Polyoxin D and Nikkomycin Z. Altogether, our results demonstrate that the two SR-like protein kinases in C. albicans have divergent functions: C. albicans and C. glabrata Sky1 is functionally similar to Sky1 in S. cerevisiae, whereas Sky2 regulates uptake of dipeptides.
2022-05-09 | PXD027612 | Pride
Project description:Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (~100â??1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients. To compare the RNA Seq profiles from the cortex and spinal cord of transgenic mice expressing unexpanded human C9orf72 (F08, n=4), expanded human C9orf72 (F112, n=3/4), and nontransgenic controls (n=4).
2016-02-10 | E-GEOD-77720 | biostudies-arrayexpress
Project description:Expanded intronic GGGGCC repeats in C9ORF72 produce several dipeptides, from which the two that contain arginine, (PR)n and (GR)n, accumulate at nucleoli and kill cells. While this toxicity plays an important role in ALS pathogenesis, its mechanism remains unknown. We here show that PR dipeptides bind avidly to DNA and RNA, so that any cellular reaction involving nucleic acids is impaired by the dipeptides. Consistently, PR-induced cell death can be rescued by addition of non-coding oligonucleotides. Interestingly, the effects of PR dipeptides are to a large extent mimicked by protamine, a sperm-specific Arg-rich protein, and the toxicity of either protamine or PR dipeptides is rescued by the anticoagulant heparin. We propose that the generalized coating of nucleic acids by Arg-rich peptides accounts for the toxicity of C9ORF72 mutations in ALS.
2021-04-12 | PXD014085 | Pride
Project description:Expanded intronic GGGGCC repeats in C9ORF72 produce several dipeptides, from which the two that contain arginine, (PR)n and (GR)n, accumulate at nucleoli and kill cells. While this toxicity plays an important role in ALS pathogenesis, its mechanism remains unknown. We here show that PR dipeptides bind avidly to DNA and RNA, so that any cellular reaction involving nucleic acids is impaired by the dipeptides. Consistently, PR-induced cell death can be rescued by addition of non-coding oligonucleotides. Interestingly, the effects of PR dipeptides are to a large extent mimicked by protamine, a sperm-specific Arg-rich protein, and the toxicity of either protamine or PR dipeptides is rescued by the anticoagulant heparin. We propose that the generalized coating of nucleic acids by Arg-rich peptides accounts for the toxicity of C9ORF72 mutations in ALS.
2021-04-12 | PXD010555 | Pride
Project description:Primary objectives: percentuale di pazienti che saranno sottoposti a resezione completa
Primary endpoints: Lo Studio si propone di aumentare la percentuale di resecabilita’ di pazienti con metastasi epatiche da carcinoma del colon retto.
| 2517634 | ecrin-mdr-crc