Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA320078 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3467110_1.fastq.gz | Fastqsanger.gz | |||
| SRR3467110_2.fastq.gz | Fastqsanger.gz | |||
| SRR3467111_1.fastq.gz | Fastqsanger.gz | |||
| SRR3467111_2.fastq.gz | Fastqsanger.gz | |||
| SRR3467112_1.fastq.gz | Fastqsanger.gz |
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Project description:Human endothelial colony-forming cells (ECFCs) represent one of the most promising sources of adult stem cells for vascular regeneration after ischemia. Yet, the molecular mechanism underlying the unique properties of these cells to repair damaged blood vessels remains unclear, and new strategies to improve their regenerative function are needed. Here, we demonstrate that ex vivo treatment of ECFCs with a combination of epigenetic drugs (i.e. the histone H3K27 demethylase inhibitor GSK-343 and the histone deacetylase inhibitor panobinostat) improves the migration of these cells and their capacity to form capillary-like networks while also increasing their resistance to serum starvation-induced apoptosis. Furthermore, the kinetic of blood flow recovery is significantly increased upon transplantation of drug-treated ECFCs in a pre-clinical model of hind-limb ischemia. Gene expression profiling by RNA-sequencing reveals that these effects are mediated through the simultaneous activation of several major pro-angiogenic signaling pathways including VEGFR, CXCR4, WNT, NOTCH and SHH. At the molecular level, we provide evidence that the two drugs work through complementary mechanisms that entail the resolving of bivalently marked genes characterized by the presence of both negative (H3K27me3) and positive (H3K4me3 and H3-Ac) histone modifications to create a transcriptionally permissive chromatin environment. Thus, ex vivo treatment with epigenetic drugs increases the vascular repair properties of ECFCs through transient activation of major pro-angiogenic signaling pathways.
2017-09-05 | GSE80819 | GEO
Project description:Rational: EZH2, an epigenetic enzyme, acts as a transcriptional repressor for genes dysregulated after myocardial infarction (MI). Objective: This study aims to assess the benefits of GSK-343 (EZH2 inhibitor) on cardiac function and lipid metabolism after MI. Methods: Mice were treated daily with vehicle or GSK-343 for 7 days after MI and we evaluated cardiac function (echocardiography), gene expression profiling (RNA-seq) and circulating lipidome (untargeted lipidomics). Results: The 28% MI decreased ejection fraction (EF) was improved by 20% with GSK-343. RNA-seq analysis revealed wide changes in MI normalized with GSK-343: 16 mitochondrial DNA-encoded genes, 57 genes related to mitochondrial function and 15 to lipid metabolism among the 561 down-regulated genes (FC 0.5 and 2; p=10-4). In plasma, while MI enhanced 18 triglycerides (1.24-2.43-fold; p<0.05) and decreased 32 choline glycerophospholipids (PC; 0.55-0.81-fold, p<0.05), GSK-343 normalized these perturbations. In MI, some of these lipids positively correlated with EF (e.g. PC40:6; R=0.84, p=0.004) or with cardiac hypertrophy (e.g. DG18:1_18:2; R=0.81, p=0.007) and GSK-343 abolished most of these correlations. Conclusion: Our study suggests that inhibiting EZH2 is of therapeutic interest to normalize lipid metabolism perturbations and improve cardiac function after MI.
2026-01-01 | GSE304090 | GEO
Project description:The canonical function of EZH2 is methylation of H3K27, although important non-canonical roles have recently been described. EZH2 mutation or deregulated expression has been conclusively demonstrated in the pathogenesis and response to treatment of acute myeloid leukemia (AML), thus making it an attractive therapeutic target. In this study, we therefore investigated whether inhibition of EZH2 might also improve the response of non-APL AML cells to ATRA-based therapy. We focused on GSK-343, a pyridone-containing S-adenosyl-L-methionine (SAM) cofactor-competitive EZH2 inhibitor that is representative of its class, and HKMTI-1-005, a substrate-competitive dual inhibitor targeting EZH2 and the closely related G9A/GLP H3K9 methyltransferases. We found that treatment with HKMTI-1-005 phenocopied EZH2 knockdown and was more effective in inducing myeloid differentiation (both in the absence and presence of ATRA) than GSK-343, despite the efficacy of GSK-343 in terms of abolishing H3K27 trimethylation. Furthermore, transcriptomic analysis revealed that in contrast to treatment with GSK-343, HKMTI-1-005 upregulated the expression of myeloid differentiation pathway genes with and without ATRA, while downregulating genes associated with a hematopoietic stem cell phenotype. Expression data (by HuGene 1.0 ST Affymetrix arrays) from HL-60 AML cells treated for 3 days with EZH2 inhibitors (10µM GSK343 or 2.5µM HKMTI-1-005) with or without AtRA (0.1µM) as well as data from HL-60 cells stabelly transduced with EZH2 KD (shEZH2#1 and shEZH2#2) or control (Scr) lentiviruses, selected and expanded for ~20 days with or without treatment with 0.1µM AtRA for 3 days.
2023-03-10 | GSE222616 | GEO
Project description:Comparative analysis of TAL1 binding in TSA-treated versus non-treated Endothelial Colony Forming Cells (ECFCs)
| PRJNA231952 | ENA
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:We have sequenced miRNA libraries from human embryonic, neural and foetal mesenchymal stem cells. We report that the majority of miRNA genes encode mature isomers that vary in size by one or more bases at the 3’ and/or 5’ end of the miRNA. Northern blotting for individual miRNAs showed that the proportions of isomiRs expressed by a single miRNA gene often differ between cell and tissue types. IsomiRs were readily co-immunoprecipitated with Argonaute proteins in vivo and were active in luciferase assays, indicating that they are functional. Bioinformatics analysis predicts substantial differences in targeting between miRNAs with minor 5’ differences and in support of this we report that a 5’ isomiR-9-1 gained the ability to inhibit the expression of DNMT3B and NCAM2 but lost the ability to inhibit CDH1 in vitro. This result was confirmed by the use of isomiR-specific sponges. Our analysis of the miRGator database indicates that a small percentage of human miRNA genes express isomiRs as the dominant transcript in certain cell types and analysis of miRBase shows that 5’ isomiRs have replaced canonical miRNAs many times during evolution. This strongly indicates that isomiRs are of functional importance and have contributed to the evolution of miRNA genes
2014-08-06 | GSE58734 | GEO
Project description:Human ECFCs: Cord Blood vs Peripehral Blood ECFCs
| PRJNA322029 | ENA
Project description:As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain.A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development.Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines.
| S-EPMC4686780 | biostudies-literature
Project description:PurposeWe investigated the evidence of recent positive selection in the human phototransduction system at single nucleotide polymorphism (SNP) and gene level.MethodsSNP genotyping data from the International HapMap Project for European, Eastern Asian, and African populations was used to discover differences in haplotype length and allele frequency between these populations. Numeric selection metrics were computed for each SNP and aggregated into gene-level metrics to measure evidence of recent positive selection. The level of recent positive selection in phototransduction genes was evaluated and compared to a set of genes shown previously to be under recent selection, and a set of highly conserved genes as positive and negative controls, respectively.ResultsSix of 20 phototransduction genes evaluated had gene-level selection metrics above the 90th percentile: RGS9, GNB1, RHO, PDE6G, GNAT1, and SLC24A1. The selection signal across these genes was found to be of similar magnitude to the positive control genes and much greater than the negative control genes.ConclusionsThere is evidence for selective pressure in the genes involved in retinal phototransduction, and traces of this selective pressure can be demonstrated using SNP-level and gene-level metrics of allelic variation. We hypothesize that the selective pressure on these genes was related to their role in low light vision and retinal adaptation to ambient light changes. Uncovering the underlying genetics of evolutionary adaptations in phototransduction not only allows greater understanding of vision and visual diseases, but also the development of patient-specific diagnostic and intervention strategies.
| S-EPMC3743458 | biostudies-literature