Establishing reliable biomarkers for assessing and validating clinical diagnosis at early prodromal stages of Parkinsons disease is crucial for developing therapies to slow or halt disease progression. Here, we present the largest study to date using whole blood gene expression profiling from over 500 individuals to identify an 87-gene blood-based signature. Our gene signature effectively differentiates between idiopathic PD patients and controls in both a validation cohort and an independent test cohort, and further highlights mitochondrial metabolism and ubiquitination/proteasomal degradation as potential pathways disrupted in Parkinsons disease.
Analysis of blood-based gene expression in idiopathic Parkinson disease.
Sex, Specimen part, SubjectView Samples
The cellular response to DNA damage is vital for maintaining genomic stability and preventing undue cell death or cancer formation. The DNA damage response (DDR), most robustly mobilized by double-strand breaks (DSBs), rapidly activates an extensive signaling network that affects numerous cellular systems, leading to cell survival or programmed cell death. A major component of the DDR is the widespread modulation of gene expression. We analyzed transcriptional responses to ionizing radiation (IR) in 5 human cell lines to elucidate the scope of this response and identify its gene targets. According to the mRNA expression profiles most of the responses were cell line-specific. Data analysis identified significant enrichment for p53 target genes and cell cycle-related pathways among groups of up-regulated and down-regulated genes, respectively.
Transcriptional modulation induced by ionizing radiation: p53 remains a central player.
Cell line, TimeView Samples
Individual genetic variation affects gene expression and cell phenotype by acting within complex molecular circuits, but this relationship is still largely unknown. Here, we combine genomic and meso-scale profiling with novel computational methods to detect genetic variants that affect the responsiveness of gene expression to stimulus (responsiveness QTLs) and position them in circuit diagrams. We apply this approach to study individual variation in transcriptional responsiveness to three different pathogen components in the model response of primary bone marrow dendritic cells (DCs) from recombinant inbred mice strains. We show that reQTLs are common both in cis (affecting a single target gene) and in trans (pleiotropically affecting co-regulated gene modules) and are specific to some stimuli but not others. Leveraging the stimulus-specific activity of reQTLs and the differential responsiveness of their associated targets, we show how to position reQTLs within the context of known pathways in this regulatory circuit. For example, we find that a pleiotropic trans-acting genetic factor in chr1:129-165Mb affects the responsiveness of 35 anti-viral genes only during an anti-viral like stimulus. Using RNAi we uncover RGS16 the likely causal gene in this interval, and an activator of the antiviral response. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in other complex circuits in primary mammalian cells.
Deciphering molecular circuits from genetic variation underlying transcriptional responsiveness to stimuli.
Age, Specimen partView Samples
This SuperSeries is composed of the SubSeries listed below.
PrtT-regulated proteins secreted by Aspergillus fumigatus activate MAPK signaling in exposed A549 lung cells leading to necrotic cell death.
Specimen part, Cell line, TreatmentView Samples
Our data mark GIP as a beneficial immunoregulator during obesity and suggest a novel untapped therapeutic potential for specific targeted GIP analogs.
Glucose-Dependent Insulinotropic Polypeptide Receptor Deficiency Leads to Impaired Bone Marrow Hematopoiesis.
Sex, Specimen partView Samples
This work explores the therapeutic potential for the translation initiation factor eIF4E in multiple myeloma (MM). We show that targeting eIF4E is deleterious to MM cells and causes reduction of targets with established importance to the disease progression. We demonstrate that eIF4E inhibition may be achieved by treating the MM cells with the already clinically employed anti-viral drug Ribavirin.
No associated publication
Specimen part, Cell lineView Samples
Genome-wide mRNA expression in brains of wild-type and eIF2B-R132H/R132H mutant mice (Geva et al., BRAIN 133 (8), 2010) profiled at postnatal (P) days 1, 18 and 21 to reflect the early proliferative stage prior to white matter establishment (P1) and the peak of oligodendrocye differentiation and myelin synthesis (P18 and P21).
A point mutation in translation initiation factor eIF2B leads to function--and time-specific changes in brain gene expression.
Specimen partView Samples