An efficient innate immune recognition of the intracellular parasite T. cruzi is crucial for host protection against development of Chagas disease, which often leads to multiple organ damage, particularly the heart leading to cardiomyopathy. Mechanisms modulated by MyD88 have been shown to be necessary for resistance against T, cruzi infection. Recently, Nod-like receptors have been shown to play an important role as innate immune sensors, particularly as they relate to inflammasome function, caspase activation, and inflammatory cytokine production. In this study, we aimed to investigate the participation of innate immune responses in general, and inflammasomes in particular, in heart inflammation and cardiac damage upon infection with the T. cruzi parasite.
Apoptosis-associated speck-like protein containing a caspase recruitment domain inflammasomes mediate IL-1β response and host resistance to Trypanosoma cruzi infection.
Specimen part
View SamplesChronic obstructive pulmonary disease (COPD) is an inflammatory lung disease with complex pathological features and largely unknown etiologies. Identification and validation of biomarkers for this disease could facilitate earlier diagnosis, appreciation of disease subtypes and/or determination of response to therapeutic intervention. To identify gene expression markers for COPD, we performed genome-wide expression profiling of lung tissue from 56 subjects using the Affymetrix U133 Plus 2.0 array. Lung function measurements from these subjects ranged from normal, un-obstructed to severely obstructed. Analysis of differential expression between cases (FEV1<70%, FEV1/FVC<0.7) and controls (FEV1>80%, FEV1/FVC>0.7) identified a set of 65 probe sets representing discrete markers associated with COPD. Correlation of gene expression with quantitative measures of airflow obstruction (FEV1 or FEV1/FVC) identified a set of 220 probe sets. A total of 31 probe sets were identified that showed evidence of significant correlation with quantitative traits and differential expression between cases and controls.
Molecular biomarkers for quantitative and discrete COPD phenotypes.
Race
View SamplesWe report the application of high-throughput RNA sequencing to the human prefrontal cortex. The brain dataset was obtained by sequencing total RNAs extracted from the dorsolateral prefrontal cortex of five deceased human patients with no apparent pathology, followed by depletion of ribosomal RNA to obtain all non-rRNA coding and non-coding RNAs in the human brain transcriptome. Overall design: Five samples were sequenced, four coming from frozen brain tissue (frontal cortex) of deceased female human patients with no remarkable pathology, and one from a male patient with no remarkable pathology.
HAMR: high-throughput annotation of modified ribonucleotides.
Sex, Specimen part, Subject
View SamplesThe surprising observation that virtually the entire human genome is transcribed means we know very little about the function of many emerging classes of RNAs, except their astounding diversity. Traditional RNA function prediction methods rely on sequence or alignment information, which are limited in their ability to classify classes of non-coding RNAs (ncRNAs). To address this, we developed CoRAL, a machine learning-based approach for classification of RNA molecules. CoRAL uses biologically interpretable features including fragment length, cleavage specificity, and antisense transcription to distinguish between different ncRNA classes. We evaluated CoRAL using genome-wide small RNA sequencing (smRNA-seq) datasets from two human tissue types (brain and skin [GSE31037]), and were able to classify six different types of RNA transcripts with 79~80% accuracy in cross-validation experiments, and with 71~73% accuracy when CoRAL uses one tissue type for training and the other as validation. Analysis by CoRAL revealed that long intergenic ncRNAs, small cytoplasmic RNAs, and small nuclear RNAs show more tissue specificity, while microRNAs, small nucleolar, and transposon-derived RNAs are highly discernible and consistent across the two tissue types. The ability to consistently annotate loci across tissue types demonstrates the potential of CoRAL to characterize ncRNAs using smRNA-seq data in less characterized organisms. Overall design: Four samples were sequenced, each one coming from frozen brain tissue (frontal cortex) of a deceased female human patient with no remarkable pathology.
HAMR: high-throughput annotation of modified ribonucleotides.
Sex, Specimen part, Disease, Disease stage, Subject
View SamplesOne of the most common smoking-related diseases, chronic obstructive pulmonary disease (COPD), results from a dysregulated, multi-tissue inflammatory response to cigarette smoke. We hypothesized that systemic inflammatory signals in genome-wide blood gene expression can identify clinically important COPD-related disease subtypes, and we leveraged pre-existing gene interaction networks to guide unsupervised clustering of blood microarray expression data. Using network-informed non-negative matrix factorization, we analyzed genome-wide blood gene expression from 229 former smokers in the ECLIPSE Study, and we identified novel, clinically relevant molecular subtypes of COPD. These network-informed clusters were more stable and more strongly associated with measures of lung structure and function than clusters derived from a network-nave approach, and they were associated with subtype-specific enrichment for inflammatory and protein catabolic pathways. These clusters were successfully reproduced in an independent sample of 135 smokers from the COPDGene Study.
COPD subtypes identified by network-based clustering of blood gene expression.
Sex, Age
View SamplesRNA-binding proteins participate in a complex array of post-transcriptional controls essential to cell-type specification and somatic development. Despite their detailed biochemical characterizations, the degree to which each RNA-binding protein impacts on mammalian embryonic development remains incompletely defined and the level of functional redundancy among subsets of these proteins remains open to question. The poly-(C) binding proteins, Pcbp's (aCPs, hnRNPEs), are encoded by a highly conserved and broadly expressed gene family. The two major Pcbp isoforms, Pcbp2 and Pcbp1, are robustly expressed in a wide range of tissues and exert both nuclear and cytoplasmic controls over gene expression. Here we report that Pcbp1-null embryos are rendered nonviable in the peri-implantation stage. In contrast, Pcbp2-null embryos survive until mid-gestation at which time they undergo a loss in viability associated with cardiovascular and hematopoietic abnormalities. Adult mice heterozygous for either Pcbp1 or Pcbp2 null alleles display a mild and non-disruptive growth defect. These data reveal that Pcbp1 and Pcbp2 are individually essential for mouse embryonic development and post-natal growth, reveal a non-redundant in vivo role for Pcpb2 in hematopoiesis, and provide direct evidence that Pcbp1, a retrotransposed derivative of Pcpb2, has evolved essential function(s) in the mammalian genome. Overall design: mRNA-seq on fetal liver tissue from 12.5 days post coitum. 4 replicates of WT and 3 replicates of PCBP2 Knockout
Poly(C)-Binding Protein Pcbp2 Enables Differentiation of Definitive Erythropoiesis by Directing Functional Splicing of the Runx1 Transcript.
Age, Subject
View SamplesPreviously we and other teams have found that 20E modulates the induction and expression of antimicrobial peptides (AMPs) in immune-challenged Drosophila cell culture or whole animals.
Ecdysone triggered PGRP-LC expression controls Drosophila innate immunity.
Specimen part
View SamplesJuvenile hormone (JH) and 20-hydroxy-ecdysone (20E) are highly versatile hormones, coordinating development, growth, and reproduction in insects. Pulses of 20E provide key signals for initiating developmental and physiological transitions, while JH promotes or inhibits these signals in a stage-specific manner. Previous evidence suggests that JH and 20E might modulate innate immunity, but whether and how these hormones interact to regulate the immune response remains unclear. Here we show that JH and 20E have antagonistic effects on the expression of antimicrobial peptides (AMPs) in Drosophila melanogaster. In S2* cells challenged with bacterial peptidoglycans, 20E induces promoter activity and expression of AMPs in a dose-dependent manner, while JH III and its synthetic analogs (JHa) methoprene and pyriproxyfen abolish this 20E-dependent response. Using microarrays and GFP reporter gene assays in adult flies, we confirm that JH is a hormonal immuno-suppressor in vivo. When silencing both partners of the ecdysone receptor (EcR ) / ultraspiracle (USP) heterodimer with RNAi in S2* cells, 20E fails to activate Diptericin (Dpt) expression, suggesting that 20E regulates expression of this gene through EcR / USP signaling. In contrast, silencing methoprene-tolerant (MET), a candidate JH receptor, does not impair the immuno-suppressive action of JH III and JHa, indicating that in this context MET does not function as a JH receptor. Our results suggest that the balance of 20E and JH is a major determinant of immune homeostasis in insects.
Hormonal regulation of the humoral innate immune response in Drosophila melanogaster.
Sex
View SamplesGenome-wide association studies (GWAS) have been pivotal to increasing our understanding of intestinal disease. However, the mode by which genetic variation results in phenotypic change remains largely unknown, with many associated polymorphisms likely to modulate gene expression. Analyses of expression quantitative trait loci (eQTL) to date indicate that as many as 50% of these are tissue specific. Here we report a comprehensive eQTL scan of intestinal tissue.
Expression quantitative trait loci analysis identifies associations between genotype and gene expression in human intestine.
Sex, Disease
View SamplesWe have investigated the effect of RRP6 depletion on the transcriptome of S2 cells using Illumina deep RNA sequencing. We have also carried out Illumina ChIP-seq analysis of RRP6 genome occupancy in control S2 cells (GFP-KD) and in cells depleted of SU(VAR)3-9. Overall design: 8 samples total; 4 RNA-Seq samples (1 RRP6-KD and 1 GFP-KD, 2 biological replicates each); and 4 ChIP-Seq samples (RRP6 IP in GFP-KD and in Su(var)3-9-KD conditions; plus their respective Input samples).
An Interaction between RRP6 and SU(VAR)3-9 Targets RRP6 to Heterochromatin and Contributes to Heterochromatin Maintenance in Drosophila melanogaster.
Subject
View Samples