Chronic kidney disease (CKD) is the gradual, asymptomatic loss of kidney function and current tests only identify it when significant loss has already happened. Using RNA sequencing in a mouse model of folic acid (FA) induced nephropathy, here we report the identification of 10 genes that track kidney fibrosis development, the common pathological finding in CKD patients. The gene expression of all 10 candidates was confirmed to be significantly high (~ 10-150 fold) in three well-established and mechanistically distinct mouse models of kidney fibrosis. Protein expression was also high in the FA model as well as patients with biopsy-proven kidney fibrosis. The specificity of these 10 candidates for kidney fibrosis was demonstrated by showing a very modest (~ 2-5 fold) increase in the mouse models of acute kidney injury as well as following liver fibrosis in mice and humans. Using targeted selected reaction monitoring mass spectrometry (SRM-MS) we found that 3 out of 10, cadherin 11 (CDH11), mannose receptor C1 (MRC1), phospholipid transfer protein (PLTP), are detectable in human urine. Furthermore, the levels of CDH11 and MRC1 are able to distinguish patients with chronic kidney disease from healthy individuals (n = 78, p<0.01). In summary, we report the identification of CDH11 and MRC1 as novel non-invasive biomarkers of CKD. Overall design: mRNA sequencing of mouse kidney before and at various time points (1,2,3,7 & 14 days) after intraperitoneal treatment with folic acid.
RNA Sequencing Identifies Novel Translational Biomarkers of Kidney Fibrosis.
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A global transcriptomic view of the multifaceted role of glutathione peroxidase-1 in cerebral ischemic-reperfusion injury.
Treatment
View SamplesIschemic stroke triggers severe focal hypoperfusion accompanied with deprivation of oxygen and glucose to the cerebral tissue, together with loss of ATP, depolorization of neurons, elevated extracellular potassium concentration, and subsequently leads to excitotoxicity as well as increased oxidative stress promoting microvascular injury, blood-brain-barrier deregulation, post-ischemic inflammation and eventually the consequential neurological deficit. Although reperfusion of ischemic brain tissue is critical for restoring normal function, it can paradoxically result in secondary damage, called ischemia/reperfusion (I/R) injury.
A global transcriptomic view of the multifaceted role of glutathione peroxidase-1 in cerebral ischemic-reperfusion injury.
Treatment
View SamplesT follicular helper (Tfh) cells are a subset of CD4+ T helper (Th) cells that migrate into germinal centers and promote B cell maturation into memory B and plasma cells. Tfh cells are necessary for promotion of protective humoral immunity following pathogen challenge, but when aberrantly regulated, drive pathogenic antibody formation in autoimmunity and undergo neoplastic transformation in angioimmunoblastic T-cell lymphoma and other primary cutaneous T-cell lymphomas. Limited information is available on the expression and regulation of genes in human Tfh cells. Using a fluorescence activated cell sorting-based strategy, we obtained primary Tfh and non-Tfh T effector (Teff) cells from tonsils and prepared genome-wide maps of active, intermediate, and poised enhancers determined by ChIP-seq, with parallel transcriptome analyses determined by RNA-seq. Tfh cell enhancers were enriched near genes highly expressed in lymphoid cells or involved in lymphoid cell function, with many mapping to sites previously associated with autoimmune disease in genome-wide association studies. A group of active enhancers unique to Tfh cells associated with differentially expressed genes was identified. Fragments from these regions directed expression in reporter gene assays. These data provide a significant resource for studies of T lymphocyte development and differentiation and normal and perturbed Tfh cell function. Overall design: Using a fluorescence activated cell sorting-based strategy, we obtained primary Tfh and non-Tfh T effector (Teff) cells from tonsils and prepared genome-wide maps of active, intermediate, and poised enhancers determined by ChIP-seq, with parallel transcriptome analyses determined by RNA-seq.
Global transcriptome analysis and enhancer landscape of human primary T follicular helper and T effector lymphocytes.
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View SamplesWe report the application of RNA sequencing technology for high-throughput profiling of gene expression responses to human rhinovirus infection at 24 hours in air-liquid interface human airway epithelial cell cultures derived from 6 asthmatic and 6 non-asthmatic donors. RNA-seq analysis identified sets of genes associated with asthma specific viral responses. These genes are related to inflammatory pathways, epithelial remodeling and cilium assembly and function, including those described previously (e.g. CCL5, CXCL10 and CX3CL1), and novel ones that were identified for the first time in this study (e.g. CCRL1, CDHR3). We concluded that air liquid interface cultured human airway epithelial cells challenged with live HRV are a useful in vitro model for the study of rhinovirus induced asthma exacerbation, given that our findings are consistent with clinical data sets. Furthermore, our data suggest that abnormal airway epithelial structure and inflammatory signaling are important contributors to viral induced asthma exacerbation. Overall design: Differentiated air-liquid interface cultured human airway epithelial cell mRNA profiles from 6 asthmatic and 6 non-asthmatic donors after 24 hour treatment with either HRV or vehicle control were generated by deep sequencing, using Illumina HiSeq 2000.
Phenotypic responses of differentiated asthmatic human airway epithelial cultures to rhinovirus.
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View SamplesInvestigating neuronal and photoreceptor regeneration in the retina of zebrafish has begun to yield insights into both the cellular and molecular means by which this lower vertebrate is able to repair its central nervous system. However, knowledge about the signaling molecules in the local microenvironment of a retinal injury and the transcriptional events they activate during neuronal death and regeneration is still lacking. To identify genes involved in photoreceptor regeneration, we combined light-induced photoreceptor lesions, laser-capture microdissection (LCM) of the outer nuclear layer (ONL) and analysis of gene expression to characterize transcriptional changes for cells in the ONL as photoreceptors die and are regenerated. Using this approach, we were able to characterize aspects of the molecular signature of injured and dying photoreceptors, cone photoreceptor progenitors and microglia within the ONL. We validated changes in gene expression and characterized the cellular expression for three novel, extracellular signaling molecules that we hypothesize are involved in regulating regenerative events in the retina.
Identification of the molecular signatures integral to regenerating photoreceptors in the retina of the zebra fish.
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View SamplesInadequate protein intake initiates an accommodative response with adverse changes in skeletal muscle function and structure. mRNA level changes due to short-term inadequate dietary protein might be an early indicator of accommodation. The aims of this study were to assess the effects of dietary protein and the diet-by-age interaction on the skeletal muscle transcript profile. Self-organizing maps were used to determine expression patterns across protein trials.
The skeletal muscle transcript profile reflects accommodative responses to inadequate protein intake in younger and older males.
Sex
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The origins of breast cancer prognostic gene expression profiles.
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View SamplesSignaling by the cytokine LIF and its downstream transcription factor, STAT3, prevents differentiation of pluripotent embryonic stem cells (ESCs) by opposing MAP kinase signaling. This contrasts with most cell types where STAT3 signaling induces differentiation. We find that STAT3 binding across the pluripotent genome is dependent upon Brg, the ATPase subunit of a specialized chromatin remodeling complex (esBAF) found in ESCs. Brg is required to establish chromatin accessibility at STAT3 binding targets, in essence preparing these sites to respond to LIF signaling. Moreover, Brg deletion leads to rapid Polycomb (PcG) binding and H3K27me3-mediated silencing of many Brg-activated targets genome-wide, including the target genes of the LIF signaling pathway. Hence, one crucial role of Brg in ESCs involves its ability to potentiate LIF signaling by opposing PcG. Contrary to expectations, Brg also facilitates PcG function at classical PcG target including all four Hox loci, reinforcing their repression in ESCs. These findings reveal that esBAF does not simply antagonize PcG, but rather, the two chromatin regulators act both antagonistically and synergistically with the common goal of supporting pluripotency.
esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function.
Cell line, Treatment
View SamplesThe hormone prolactin is implicated in the pathogenesis of breast cancer, and a subset of prolactin-induced gene expression is mediated by CypA activity.
Inhibition of the Activity of Cyclophilin A Impedes Prolactin Receptor-Mediated Signaling, Mammary Tumorigenesis, and Metastases.
Sex, Specimen part, Disease, Disease stage, Cell line
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