Transcription of the pain‐related TRPV1 gene requires Runx1 and C/EBPβ factors

Transient Receptor Potential Vanilloid type 1 channel (TRPV1) is an important endogenous transducer of noxious heat and chemical stimuli and is required during development of inflammatory hypersensitivity. The transcription factor Runx1 is known to play a relevant role in sensory neuron differentiation as it controls the expression of several sensory nociceptive receptors, including TRPV1. Here, we show that Runx1 up-regulates TRPV1 transcription activity by interacting directly with the proximal TRPV1 gene promoter sequence. Importantly, C/EBPβ a well-established heterodimer partner of Runx1 also binds to the TRPV1 promoter and cooperates with Runx1 to further stimulate TRPV1 transcription. Our results support a mechanism where Runx1-C/EBPβ-containing transcription regulatory complexes are recruited to the TRPV1 gene promoter to modulate TRPV1 expression in dorsal root ganglia neurons.3.874 JCR (2013) Q1, 14/81 Physiology; Q2, 77/185 Cell biolog

Overrepresentation of Glutamate Signaling in Alzheimer's Disease: Network-Based Pathway Enrichment Using Meta-Analysis of Genome-Wide Association Studies

<div><p>Genome-wide association studies (GWAS) have successfully identified several risk loci for Alzheimer's disease (AD). Nonetheless, these loci do not explain the entire susceptibility of the disease, suggesting that other genetic contributions remain to be identified. Here, we performed a meta-analysis combining data of 4,569 individuals (2,540 cases and 2,029 healthy controls) derived from three publicly available GWAS in AD and replicated a broad genomic region (>248,000 bp) associated with the disease near the APOE/TOMM40 locus in chromosome 19. To detect minor effect size contributions that could help to explain the remaining genetic risk, we conducted network-based pathway analyses either by extracting gene-wise p-values (GW), defined as the single strongest association signal within a gene, or calculated a more stringent gene-based association p-value using the extended Simes (GATES) procedure. Comparison of these strategies revealed that ontological sub-networks (SNs) involved in glutamate signaling were significantly overrepresented in AD (p<2.7×10⁻¹¹, p<1.9×10⁻¹¹; GW and GATES, respectively). Notably, glutamate signaling SNs were also found to be significantly overrepresented (p<5.1×10⁻⁸) in the Alzheimer's disease Neuroimaging Initiative (ADNI) study, which was used as a targeted replication sample. Interestingly, components of the glutamate signaling SNs are coordinately expressed in disease-related tissues, which are tightly related to known pathological hallmarks of AD. Our findings suggest that genetic variation within glutamate signaling contributes to the remaining genetic risk of AD and support the notion that functional biological networks should be targeted in future therapies aimed to prevent or treat this devastating neurological disorder.</p></div

Meta-analysis 25 top hits.

<p>Chr: Chromosome; BP: Physical Position (Base Pair, NCBI 36.3/Hg18); A1: Allele 1 (Affected); A2: Allele 2 (Reference); N: Number of datasets with information; p-value: Fixed effect model p-value; OR: Odd Ratio.</p

Genome-Wide Association Studies main features.

a<p>Imputed. ^bSNPs shared between the 3 studies. ^cAD + mild cognitive impairment (MCI) individuals.</p

Glutamate positive sub-networks in ADNI-GW analysis.

<p>SN: Sub-network; GO ID: Gene ontology term ID; GIP: Genes in population; GISN: Genes in sub-network; TG: Total genes in SN; BP: Biological process; CC: Cellular component; MF: Molecular function.</p

Genome wide meta-analysis results in AD.

<p>Manhattan plot showing the p-values obtained in the meta-analysis. The end and beginning of a chromosome is denoted by the change of color pattern of the SNPs (black, grey and brown dots). Genome-wide significance threshold is denoted by a red line (5.0×10⁻⁸). The Y-axis has been truncated to show all associated SNPs inside the APOE loci and to improve visualization of suggestive associations.</p

Gene expression analysis of glutamate signaling components in selected human brain regions.

<p>Heatmap and dendrogram of normalized expression levels of the 20 genes of interest displaying significant clustering in: (A) hippocampal formation (HIF); (B) hypothalamus (HY); (C) Dorsal Thalamus (DT); and (D) white matter (WM). Heatmaps were generated using normalized Z score gene-wise expression values, which were averaged from 6 brain donor individuals (ids. H0351.2001, H0351.2002, H0351.1009, H0351.1012, H0351.1015 and H0351.1016). Bright red and green color indicates high (Z>2) and low expression (Z<2). Highly correlated gene clusters (Euclidean distance correlation coefficient r>0.7) are denoted by colored lines in the dendrograms: green clusters, indicates low expression patterns; red clusters show high levels of expression of correlated genes. Gene expression patterns in the corresponding substructures are shown for HIF: Dentate Gyrus (DG); Cornu Ammonis 1 (CA1); Cornu Ammonis 2 (CA2); Cornu Ammonis 3 (CA3); Cornu Ammonis 4 (CA4) and Subiculum (S). For HY: Anterior Hypothalamic Area (AHA); Lateral hypothalamic Area (LHA); Paraventricular Nucleus of the Hypothalamus (PVH); Supraoptic Nucleus (SO); Lateral Hypothalamic Area, Mammillary Region (LHM); Mammillary Body (MB); Posterior Hypothalamic Area (PHA); Supramammillary Nucleus (SuM); Tuberomammillary Nucleus (TM); Preoptic Region (PrOR); Arcuate Nucleus of the Hypothalamus (ARH); Dorsomedial Hypothalamic Nucleus (DMH); Lateral Hypothalamic Area, Tuberal Region (LHT); Lateral Tuberal Nucleus (LTu); Perifornical Nucleus (PeF); Ventromedial Hypothalamic Nucleus (VMH). For DT: Anterior Group of Nuclei (DTA); Caudal Group of intralaminar Nuclei (ILc); Dorsal Lateral Geneiculate Nucleus (LGd); Lateral Group of Nuclei, Dorsal Division (DTLd); Lateral Group of Nuclei, Ventral Division (DTLv); Medial Geniculate Complex (MG); Medial Group of Nuclei (DTM); Posterior Group of Nuclei (DTP); Rostral Group of Intralaminar Nuclei (ILr). For WM: Cc: Corpus callosum; Cgb: Cingulum bundle.</p

GO terms enriched in Meta-GW and Meta-GATES top 3 Sub-Networks.

<p>SN: Sub-network; GO ID:Gene ontology term ID; GIP: Genes in population; GISN: Genes in sub-network; TG: Total genes in SN; BP: Biological process; CC:Cellular component; MF: Molecular function.</p

SN search results.

<p>(A) The number of significant SNs (size <50 and score>3) in Meta-GW (light green) and Meta-GATES (dark green) is shown compared with same values permuted across the FPAN: Meta-GW-Permuted (light grey) and Meta-GATES-Permuted (dark grey). (B) Score comparison of the top 10 SNs obtained in the corresponding module searches presented in (A). (C) The number of significant SNs in the replication step for ADNI-GW (light blue) and ADNI-GATES (dark blue) analysis, in comparison with their corresponding permuted controls: ADNI-GW-Permuted (light grey) and ADNI-GW-Permuted (dark grey). (D) Score comparison of the top 10 SNs obtained for each module searches presented in (C). Caped bar/points denote SD; Significant differences between real and permuted data observed in GW and GATES analysis are denoted by an asterisk and those between real and permuted data observed only in GW analysis are denoted by a plus sign (two-sided Student's t-test; p<0.01).</p