RESUMO
BACKGROUND: Individuals infected with SARS-CoV-2 vary greatly in their disease severity, ranging from asymptomatic infection to severe disease. The regulation of gene expression is an important mechanism in the host immune response and can modulate the outcome of the disease. miRNAs play important roles in post-transcriptional regulation with consequences on downstream molecular and cellular host immune response processes. The nature and magnitude of miRNA perturbations associated with blood phenotypes and intensive care unit (ICU) admission in COVID-19 are poorly understood. RESULTS: We combined multi-omics profiling-genotyping, miRNA and RNA expression, measured at the time of hospital admission soon after the onset of COVID-19 symptoms-with phenotypes from electronic health records to understand how miRNA expression contributes to variation in disease severity in a diverse cohort of 259 unvaccinated patients in Abu Dhabi, United Arab Emirates. We analyzed 62 clinical variables and expression levels of 632 miRNAs measured at admission and identified 97 miRNAs associated with 8 blood phenotypes significantly associated with later ICU admission. Integrative miRNA-mRNA cross-correlation analysis identified multiple miRNA-mRNA-blood endophenotype associations and revealed the effect of miR-143-3p on neutrophil count mediated by the expression of its target gene BCL2. We report 168 significant cis-miRNA expression quantitative trait loci, 57 of which implicate miRNAs associated with either ICU admission or a blood endophenotype. CONCLUSIONS: This systems genetics study has given rise to a genomic picture of the architecture of whole blood miRNAs in unvaccinated COVID-19 patients and pinpoints post-transcriptional regulation as a potential mechanism that impacts blood traits underlying COVID-19 severity. The results also highlight the impact of host genetic regulatory control of miRNA expression in early stages of COVID-19 disease.
Assuntos
COVID-19 , MicroRNAs , Humanos , COVID-19/genética , SARS-CoV-2/genética , Genômica , MicroRNAs/genética , RNA MensageiroRESUMO
A key challenge of functional genomics today is to generate well-annotated data sets that can be interpreted across different platforms and technologies. Large-scale functional genomics data often fail to connect to standard experimental approaches of gene characterization in individual laboratories. Furthermore, a lack of universal annotation standards for phenotypic data sets makes it difficult to compare different screening approaches. Here we address this problem in a screen designed to identify all genes required for the first two rounds of cell division in the Caenorhabditis elegans embryo. We used RNA-mediated interference to target 98% of all genes predicted in the C. elegans genome in combination with differential interference contrast time-lapse microscopy. Through systematic annotation of the resulting movies, we developed a phenotypic profiling system, which shows high correlation with cellular processes and biochemical pathways, thus enabling us to predict new functions for previously uncharacterized genes.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/genética , Desenvolvimento Embrionário/genética , Genoma , Interferência de RNA , Animais , Caenorhabditis elegans/fisiologia , Biologia Computacional , Genes de Helmintos/genética , Genômica , Fenótipo , RNA de Helmintos/genética , RNA de Helmintos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
We describe the phenotypic and molecular characterization of twinstar (tsr), an essential gene in Drosophila melanogaster. Two P-element induced alleles of tsr (tsr1 and tsr2) result in late larval or pupal lethality. Cytological examination of actively dividing tissues in these mutants reveals defects in cytokinesis in both mitotic (larval neuroblast) and meiotic (larval testis) cells. In addition, mutant spermatocytes show defects in aster migration and separation during prophase/prometaphase of both meiotic divisions. We have cloned the gene affected by these mutations and shown that it codes for a 17-kD protein in the cofilin/ADF family of small actin severing proteins. A cDNA for this gene has previously been described by Edwards et al. (1994). Northern analysis shows that the tsr gene is expressed throughout development, and that the tsr1 and tsr2 alleles are hypomorphs that accumulate decreased levels of tsr mRNA. These findings prompted us to examine actin behavior during male meiosis to visualize the effects of decreased twinstar protein activity on actin dynamics in vivo. Strikingly, both mutants exhibit abnormal accumulations of F-actin. Large actin aggregates are seen in association with centrosomes in mature primary spermatocytes. Later, during ana/telophase of both meiotic divisions, aberrantly large and misshaped structures appear at the site of contractile ring formation and fail to disassemble at the end of telophase, in contrast with wild-type. We discuss these results in terms of possible roles of the actin-based cytoskeleton in centrosome movement and in cytokinesis.
Assuntos
Divisão Celular/fisiologia , Centrossomo/fisiologia , Proteínas de Drosophila , Drosophila melanogaster/genética , Proteínas dos Microfilamentos/genética , Proteínas do Tecido Nervoso/genética , Fatores de Despolimerização de Actina , Actinas/fisiologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Divisão Celular/genética , Mapeamento Cromossômico , Clonagem Molecular , DNA , Destrina , Genes de Insetos , Humanos , Masculino , Meiose/genética , Meiose/fisiologia , Proteínas dos Microfilamentos/fisiologia , Dados de Sequência Molecular , Mutação , Proteínas do Tecido Nervoso/fisiologia , Fenótipo , Homologia de Sequência de Aminoácidos , Espermatogênese/genética , Espermatogênese/fisiologia , Transcrição GênicaAssuntos
Padronização Corporal , Proteínas de Caenorhabditis elegans , Caenorhabditis elegans/química , Drosophila melanogaster/citologia , Drosophila melanogaster/embriologia , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Western Blotting , Linhagem da Célula , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Células Germinativas/citologia , Hibridização In Situ , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Mutação , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/análise , RNA Mensageiro/genética , Homologia de SequênciaRESUMO
Protein NMR spectroscopy provides an important complement to X-ray crystallography for structural genomics, both for determining three-dimensional protein structures and in characterizing their biochemical and biophysical functions.