Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury.
Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1.
Age
View SamplesThe wheat gene Lr34 (Yr18/Pm38/Sr57/Ltn1) encodes a putative ABCG-type of transporter and is a unique source of disease resistance providing durable and partial resistance against multiple fungal pathogens. Lr34 has been found to be functional as a transgene in barley.
The wheat resistance gene Lr34 results in the constitutive induction of multiple defense pathways in transgenic barley.
Specimen part
View SamplesThe yeast Mediator complex can be divided into three modules, designated Head, Middle and Tail. Tail comprises the Med2, Med3, Med5, Med15 and Med16 protein subunits, which are all encoded by genes that are individually non-essential for viability. In cells lacking Med16, Tail is displaced from Head and Middle. However, inactivation of MED5/MED15 and MED15/MED16 are synthetically lethal, indicating that Tail performs essential functions as a separate complex even when it is not bound to Middle and Head. We have used the N-Degron method to create temperature sensitive (ts) mutants in the Mediator tail subunits Med5, Med15 and Med16 to study the immediate effects on global gene expression when each subunit is individually inactivated, and when MED5/15 or MED15/16 are inactivated together.
Functional studies of the yeast med5, med15 and med16 mediator tail subunits.
No sample metadata fields
View SamplesSynapse development and neuronal activity represent fundamental processes for the establishment of cognitive function. Structural organization as well as signalling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and misregulated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Deleterious mutations in the PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked ID and/or ASD. The structure of PTCHD1 protein is similar to the Patched (PTCH1) receptor; however, the cellular mechanisms and pathways associated with PTCHD1 in the developing brain are poorly determined. Here we show that PTCHD1 displays a C-terminal PDZ-binding motif that binds to the postsynaptic proteins PSD95 and SAP102. We also report that PTCHD1 is unable to rescue the canonical sonic hedgehog (SHH) pathway in cells depleted of PTCH1, suggesting that both proteins are involved in distinct cellular signalling pathways. We find that Ptchd1 deficiency in male mice (Ptchd1-/y) induces global changes in synaptic gene expression, affects the expression of the immediate-early expression genes Egr1 and Npas4 and finally impairs excitatory synaptic structure and neuronal excitatory activity in the hippocampus, leading to cognitive dysfunction, motor disabilities and hyperactivity. Thus our results support that PTCHD1 deficiency induces a neurodevelopmental disorder causing excitatory synaptic dysfunction. Overall design: 6 samples RNA-seq. 3 kos, 3wts.
Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse.
Specimen part, Cell line, Subject
View SamplesIdentifying the effect of the co-chaperone SGTA on global androgen receptor transcriptional activity in C4-2B prostate cancer cells with view to further elucidating the broader biological role of SGTA on other signaling pathways within prostate cancer cells
Knockdown of the cochaperone SGTA results in the suppression of androgen and PI3K/Akt signaling and inhibition of prostate cancer cell proliferation.
Specimen part, Treatment
View SamplesThe effect of transient transfection of a construct designed to over-express the androgen receptor (AR) variant AR-V7 on gene expression in MDA-MB-453 cells was assessed using Affymetrix Gene 2.0 ST arrays. Transfection of an AR-expressing construct or an empty construct served as controls.
Expression of androgen receptor splice variants in clinical breast cancers.
Cell line
View SamplesLNCaP cells were maintained in charcoal-stripped serum containing medium for 48 hours and treated with vehicle or 10 uM of UT-69, UT-155, R-UT-155, or enzalutamide. Twenty four hours after treatment, the cells were harvested, RNA was isolated and expression of genes was measured using microarray (Affymetrix Clarion S)
Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer.
Cell line
View SamplesThe abstract of the associated publication (Selga E, No V, Ciudad CJ. Biochemical Pharmacology, 2008) is the following:
Transcriptional regulation of aldo-keto reductase 1C1 in HT29 human colon cancer cells resistant to methotrexate: role in the cell cycle and apoptosis.
No sample metadata fields
View SamplesOur data demonstrate that overexpression of the polarity protein Crb3 elicits changes in MCF-10A cells that culminate in an increase in the release of amphiregulin (AR) and the subsequent activation of EGFR signaling to drive proliferation. Microarray analysis was performed to define global changes in the transcriptional landscape induced by Crb3. Results provide insight into a FERM domain protein (EBP41L4B) required for Crb3 mediated induction of proliferation.
CRB3 and the FERM protein EPB41L4B regulate proliferation of mammary epithelial cells through the release of amphiregulin.
Cell line, Treatment
View SamplesRNA sequencing was used to explore global gene expression in the chronic relapsing and secondary progressive EAE (pEAE) Biozzi ABH mouse model of MS. Spinal cord tissue RNA from pEAE Biozzi ABH mice and healthy littermate controls was sequenced. 2,072 genes were differentially expressed (q<0.05) from which 1,397 were significantly upregulated and 675 were significantly downregulated. This hypothesis-free investigation characterised the genomic changes that describe the pEAE mouse model. Overall design: Examination of 3 control and 3 pEAE mice
Characterisation of Transcriptional Changes in the Spinal Cord of the Progressive Experimental Autoimmune Encephalomyelitis Biozzi ABH Mouse Model by RNA Sequencing.
Specimen part, Subject
View Samples