scholarly journals Characterization of genomic regulation profiles in human mitral valve whole tissue to annotate genetic risk loci for mitral valve prolapse

2020 ◽  
Author(s):  
Sergiy Kyryachenko ◽  
Adrien Georges ◽  
Mengyao Yu ◽  
Takiy E. Berrandou ◽  
Patrick Bruneval ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Mitral Valve ◽  
High Throughput ◽  
Mitral Valve Prolapse ◽  
High Throughput Sequencing ◽  
Target Genes ◽  
Valve Disease ◽  
Open Chromatin ◽  
Mitral Valves ◽  
Causal Variants

Rationale: Mitral valve prolapse (MVP) is a common valve disease that leads to mitral insufficiency, heart failure and sudden death. The identification of risk loci provided insight into its genetic architecture, although the causal variants and target genes need to be fully characterized. Objective: To establish the chromatin accessibility profiles and gene regulation specificities of human mitral valve and identify functional variants and target genes at MVP loci. Methods and Results: We mapped the open chromatin accessible regions in nuclei from 11 human mitral valves by an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq). Compared to the heart tissue and cardiac fibroblasts, we found that mitral valve-specific ATAC-Seq peaks were enriched near genes involved in extracellular matrix organization, chondrocyte differentiation, and connective tissue development. The most enriched motif in mitral valve-specific open chromatin peaks was for the nuclear factor of activated T cells (NFATC) family of transcription factors, involved in valve endocardial and interstitial cells formation. We also found that MVP-associated variants (p < 10-5) observed in the current MVP GWAS were significantly enriched (p<0.05) in mitral valve open chromatin peaks. Integration of the ATAC-Seq data with GWAS loci, extensive functional annotation, and gene reporter assay revealed plausible causal variants at two risk loci: rs6723013 at the IGFBP5/TNS1 locus and rs2641440 at the SMG6/SRR locus. Circular chromosome conformation capture followed by high-throughput sequencing provided evidence for several target genes, including SRR, HIC1, and DPH1 at the SMG6/SRR locus and further supported TNS1 as the most likely target gene on Chr2. Conclusions: Here we describe unprecedented genome-wide open chromatin profiles from human mitral valves that indicates specific gene regulation profiles, compared to the heart. We also report in vitro functional evidence for potential causal variants and target genes at MVP risk loci involving established and new biological mechanisms relevant to mitral valve disease.

Abstract 13435: Characterization of Open Chromatin in Human Mitral Valves to Identify Regulatory Mechanisms at Mitral Valve Prolapse Genetic Loci

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Sergiy Kyryachenko ◽  
Adrien Georges ◽  
Mengyao Yu ◽  
Takiy Berrandou ◽  
Tony Rubio ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Mitral Valve Prolapse ◽  
Target Genes ◽  
Valve Disease ◽  
Specific Gene ◽  
Open Chromatin ◽  
Mitral Insufficiency ◽  
Mitral Valves ◽  
Causal Variants

Introduction: Mitral valve prolapse (MVP) is a common valve disease that leads to mitral insufficiency, heart failure, and sudden death. The identification of genetic risk loci provided insight into its genetic architecture, although the causal variants and target genes need to be fully characterized. Hypothesis: Functional genomic annotation, including chromatin accessibility profiles of human mitral valves, allows the characterization of variants and target genes at MVP loci. Methods: We determined open chromatin regions using the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) from surgically removed human valves and primary cultures of fibroblasts. We analyzed the spatial conformation of MVP-associated loci using circular chromatin conformation capture (4C-Seq) with candidate causal variants as viewpoints. Candidate causal variants were followed-up using reporter assays and in silico analyses. Results: We mapped the open chromatin from 11 human mitral valves and 3 primary cell cultures. We found that mitral valve-specific ATAC-Seq peaks were enriched near genes involved in extracellular matrix organization, chondrocyte differentiation, and connective tissue development. We also found that MVP-associated variants (p<10 -5 ) observed in the MVP GWAS were significantly enriched (p<0.05) in mitral valve open chromatin regions, but not in heart tissue from ENCODE. We found that rs6723013 on Chr2 belongs to a valve-specific enhancer at the IGFBP5/TNS1 locus and is the most likely causal variant at this locus. We also identified several plausible causal SNPs and, by using 4C-Seq, potential target genes ( HIC1 and DPH1 ) at the SMG6/SRR locus. Conclusions: Here we describe unprecedented genome-wide open chromatin profiles from human mitral valves that indicate specific gene regulation profiles, compared to the heart. We also report in vitro functional evidence for potential causal variants and target genes at MVP risk loci involving established and new biological mechanisms relevant to mitral valve disease.

scholarly journals Chromatin Accessibility of Human Mitral Valves and Functional Assessment of MVP Risk Loci

2021 ◽  
Author(s):  
Sergiy Kyryachenko ◽  
Adrien Georges ◽  
Mengyao Yu ◽  
Takiy Berrandou ◽  
Lilong Guo ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Target Genes ◽  
Human Fibroblasts ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Open Chromatin ◽  
Mitral Insufficiency ◽  
Mitral Valves ◽  
Gene Reporter Assay ◽  
Causal Variants

Rationale: Mitral valve prolapse (MVP) is a common valvopathy that leads to mitral insufficiency, heart failure and sudden death. Functional genomic studies in mitral valves are needed to better characterize MVP associated variants and target genes. Objective: To establish the chromatin accessibility profiles and assess functionality of variants and narrow down target genes at MVP loci. Methods and Results: We mapped the open chromatin regions in nuclei from 11 human pathogenic and 7 non-pathogenic mitral valves by an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq). Open chromatin peaks were globally similar between pathogenic and non-pathogenic valves. Compared to the heart tissue and cardiac fibroblasts, we found that MV-specific ATAC-Seq peaks are enriched near genes involved in extracellular matrix organization, chondrocyte differentiation, and connective tissue development. One of the most enriched motif in MV-specific open chromatin peaks was for the nuclear factor of activated T cells (NFATC) family of transcription factors, involved in valve endocardial and interstitial cells formation. We also found that MVP-associated variants were significantly enriched (p<0.05) in mitral valve open chromatin peaks. Integration of the ATAC-Seq data with risk loci, extensive functional annotation, and gene reporter assay suggest plausible causal variants for rs2641440 at the SMG6/SRR locus and rs6723013 at the IGFBP2/IGFBP5/TNS1 locus. CRISPR-Cas9 deletion of the sequence including rs6723013 in human fibroblasts correlated with increased expression only for TNS1. 4C-Seq experiments provided evidence for several target genes, including SRR, HIC1, and DPH1 at the SMG6/SRR locus and further supported TNS1 as the most likely target gene on Chr2. Conclusions: Here we describe unprecedented genome-wide open chromatin profiles from human pathogenic and non-pathogenic MVs and report specific gene regulation profiles, compared to the heart. We also report in vitro functional evidence for potential causal variants and target genes at MVP risk loci involving established and new biological mechanisms.

scholarly journals Identification of Exogenous Nitric Oxide-Responsive miRNAs from Alfalfa (Medicago sativa L.) under Drought Stress by High-Throughput Sequencing

Genes ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 30
Author(s):  
Yaodong Zhao ◽  
Wenjing Ma ◽  
Xiaohong Wei ◽  
Yu Long ◽  
Ying Zhao ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Drought Stress ◽  
Medicago Sativa ◽  
High Throughput ◽  
Drought Resistance ◽  
High Throughput Sequencing ◽  
Target Genes ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Medicago Sativa L

Alfalfa (Medicago sativa L.) is a high quality leguminous forage. Drought stress is one of the main factors that restrict the development of the alfalfa industry. High-throughput sequencing was used to analyze the microRNA (miRNA) profiles of alfalfa plants treated with CK (normal water), PEG (polyethylene glycol-6000; drought stress), and PEG + SNP (sodium nitroprusside; nitric oxide (NO) sprayed externally under drought stress). We identified 90 known miRNAs belonging to 46 families and predicted 177 new miRNAs. Real-time quantitative fluorescent PCR (qRT-PCR) was used to validate high-throughput expression analysis data. A total of 32 (14 known miRNAs and 18 new miRNAs) and 55 (24 known miRNAs and 31 new miRNAs) differentially expressed miRNAs were identified in PEG and PEG + SNP samples. This suggested that exogenous NO can induce more new miRNAs. The differentially expressed miRNA maturation sequences in the two treatment groups were targeted by 86 and 157 potential target genes, separately. The function of target genes was annotated by gene ontology (GO) enrichment and kyoto encyclopedia of genes and genomes (KEGG) analysis. The expression profiles of nine selected miRNAs and their target genes verified that their expression patterns were opposite. This study has documented that analysis of miRNA under PEG and PEG + SNP conditions provides important insights into the improvement of drought resistance of alfalfa by exogenous NO at the molecular level. This has important scientific value and practical significance for the improvement of plant drought resistance by exogenous NO.

scholarly journals Argonaute High-Throughput Sequencing of RNAs Isolated by Cross-Linking Immunoprecipitation Reveals a Snapshot of miRNA Gene Regulation in the Mammalian Retina

Biochemistry ◽  
2014 ◽  
Vol 53 (37) ◽  
pp. 5831-5833 ◽  
Author(s):  
Thomas R. Sundermeier ◽  
Hui Jin ◽  
Matthew L. Kleinjan ◽  
Debarshi Mustafi ◽  
Donny D. Licatalosi ◽  
...  
Keyword(s):  
Gene Regulation ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Mirna Gene ◽  
Cross Linking ◽  
Mammalian Retina

scholarly journals Mitral regurgitation in Dachshund dogs without heart murmurs

2017 ◽  
Vol 61 (3) ◽  
pp. 363-366
Author(s):  
Magdalena Garncarz ◽  
Marta Parzeniecka-Jaworska ◽  
Magdalena Hulanicka ◽  
Michał Jank ◽  
Olga Szaluś-Jordanow ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitral Valve ◽  
Mitral Regurgitation ◽  
Mitral Valve Prolapse ◽  
Mitral Valve Disease ◽  
Mitral Valve Regurgitation ◽  
Valve Disease ◽  
Valve Regurgitation ◽  
Heart Murmurs ◽  
Few Data

Abstract Introduction: Older small breed dogs are considered at risk for heart failure secondary to chronic mitral valve disease. However, few data are available on the onset of this disease in such dogs. This study was performed to determine if auscultation alone can be used to eliminate clinically relevant mitral valve regurgitation seen in echocardiography in Dachshund dogs. Material and Methods: Clinical and echocardiographic data were obtained from 107 dogs without heart murmurs. Results: The study revealed that 63.6% of the dogs had mitral regurgitation. Numbers increased with age and a larger percentage of male Dachshunds were affected than female Dachshunds. Mitral valve prolapse and thickening were mild, and the regurgitant area inextensive in most dogs. Conclusions: The study shows that mitral valve regurgitation is prevalent (63.6%) in Dachshunds without heart murmurs. Typical lesions often become apparent during echocardiographic examinations in dogs under 5 years of age.

scholarly journals Analysis of the Differential Exosomal miRNAs of DC2.4 Dendritic Cells Induced by Toxoplasma gondii Infection

2019 ◽  
Vol 20 (21) ◽  
pp. 5506
Author(s):  
Dong-Liang Li ◽  
Wei-Hao Zou ◽  
Sheng-Qun Deng ◽  
Hong-Juan Peng
Keyword(s):  
Dendritic Cells ◽  
Toxoplasma Gondii ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Target Genes ◽  
Quantitative Polymerase Chain Reaction ◽  
Biologically Active ◽  
Transferase Activity ◽  
Bioinformatics Analyses ◽  
Exosomal Mirnas

Toxoplasma gondii is an intracellular parasite that infects humans and other warm-blooded animals. Exosomes are endocytic-derived vesicles released by cells, representing an important mode of intercellular communication. In exosomes, specific molecules of proteins, lipids, and mRNAs or miRNAs have been detected, some of which are capable of transferring biologically active molecules to recipient cells. Dendritic cells (DCs) are the only antigen-presenting cells (APCs) that activate the initial immune response. In this study, high-throughput sequencing was used to analyze the exosomal miRNA profile of DC2.4 cells infected with Toxoplasma gondii for 28 h, compared with those of uninfected DC2.4 cells. Differential exosomal miRNAs (DEmiRs) from these two cell groups were analyzed. Through high-throughput sequencing, 3434 DEmiRs were obtained, and 12 stably enriched DEmiRNAs were verified by Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) and selected for further analysis. The target genes of these 12 miRNAs were predicted with online analysis software and subjected to bioinformatics analyses including protein–protein interaction (PPI) network analysis, key driver analysis (KDA), gene ontology (GO) enrichment, and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. These DEmiRs were found to be associated with a variety of biological processes and signaling pathways involved in host ubiquitin system, innate immunity, biosynthesis, and transferase activity and could be potential biomarkers for T. gondii infection.

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