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Differential Methylation Of The TRPA1 Promoter In Pain Sensitivity: MeDIP-sequencing

ABSTRACT: Chronic pain is a global public health problem, but the underlying molecular mechanisms are not fully understood. Here we examine genome-wide DNA methylation, first in 50 identical twins discordant for heat pain sensitivity and then in 50 further unrelated individuals. Whole blood DNA methylation was characterized at 5.2 million loci by MeDIP-sequencing and assessed longitudinally to identify differentially methylated regions associated with high or low pain-sensitivity (pain-DMRs). Nine meta-analysis pain-DMRs show robust evidence for association (false discovery rate 5%) with the strongest signal in the pain gene TRPA1 (P=1.2×10-13). Several pain-DMRs show longitudinal stability consistent with susceptibility effects, have similar methylation levels in brain, and altered expression in skin. Our approach identifies epigenetic changes in both novel and established candidate genes that provide molecular insights into pain and may generalize to other complex traits.

ORGANISM(S): Homo sapiens

PROVIDER: GSE52965 | GEO | 2013/12/04

SECONDARY ACCESSION(S): PRJNA230561

REPOSITORIES: GEO

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Differential Methylation Of The TRPA1 Promoter In Pain Sensitivity: MeDIP-sequencing

Project description:Chronic pain is a global public health problem, but the underlying molecular mechanisms are not fully understood. Here we examine genome-wide DNA methylation, first in 50 identical twins discordant for heat pain sensitivity and then in 50 further unrelated individuals. Whole blood DNA methylation was characterized at 5.2 million loci by MeDIP-sequencing and assessed longitudinally to identify differentially methylated regions associated with high or low pain-sensitivity (pain-DMRs). Nine meta-analysis pain-DMRs show robust evidence for association (false discovery rate 5%) with the strongest signal in the pain gene TRPA1 (P=1.2M-CM-^W10-13). Several pain-DMRs show longitudinal stability consistent with susceptibility effects, have similar methylation levels in brain, and altered expression in skin. Our approach identifies epigenetic changes in both novel and established candidate genes that provide molecular insights into pain and may generalize to other complex traits. MeDIP-sequencing in 100 individulas using a 2 stage design: paired-end MeDIP-seq in 50 monozygotic twins and single-end MeDIP-seq in 50 unrelated individuals.

2013-12-04 | E-GEOD-52965 | biostudies-arrayexpress

Project description:Differential Methylation Of The TRPA1 Promoter In Pain Sensitivity

| PRJNA230927 | ENA

Homo sapiens

Project description:Differential Methylation Of The TRPA1 Promoter In Pain Sensitivity: MeDIP-sequencing

| PRJNA230561 | ENA

Homo sapiens

Project description:Differential Methylation Of The TRPA1 Promoter In Pain Sensitivity: DNA methylation 450k array

| PRJNA230928 | ENA

hnRNPA1 SUMOylation promotes cold hypersensitivity in chronic inflammatory pain by stabilizing TRPA1 mRNA

Project description:We show here that the up-regulation of SUMO1-conjugated protein levels in a CFA-induced inflammatory pain model enhances TRPA1 mRNA stability, ultimately leading to increased expression levels. We further demonstrate that hnRNPA1 binds to TRPA1 mRNA and its SUMOylation, up-regulated in CFA-induced inflammatory pain, contributes to stabilizing TRPA1 mRNA by accumulating hnRNPA1 in the cytoplasm.

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Project description:Chronic cerebral hypoperfusion is manifested in various CNS diseases accompanied by cognitive impairment, such as dementia, however the precise mechanism of chronic cerebral hypoperfusion-induced cognitive impairment remains unknown. Recently, transient receptor potential ankyrin 1 (TRPA1), activated by oxidative stress, was reported to be involved in the cerebrovascular diseases, therefore we investigated the pathophysiological role of TRPA1 in chronic cerebral hypoperfusion using a mouse bilateral common carotid artery stenosis (BCAS) model. Early cognitive impairment and white matter injury was induced by BCAS in TRPA1-knockout (TRPA1-KO) but not wild-type (WT) mice. For further investigation into the involvement of TRPA1 in chronic cerebral hypoperfusion, we conducted RNA sequence (RNAseq) in the corpus callosum from sham- and BCAS-operated WT and TRPA1-KO mice.

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Time dependent gene expression post SNL in IPSA vs Contralateral DRGs

Project description:Chronic pain can be debilitating, and current treatments are neither universally efficacious, nor without risks. New therapeutic options are needed. Transient receptor potential (TRP) ion channels regulate inflammation and pain. Understanding how endogenous TRP ligands regulate inflammation and pain may provide insights for new therapies. Spinal nerve ligation (SNL) injury was used as a model for chronic pain. Transcriptomic and targeted lipidomic analysis of damaged tissue revealed time-dependent increases in Cyp1b1 mRNA and a concurrent accumulation of 8,9-EET and 19,20-EpDPA post injury. Production of 8,9-EET and 19,20-EpDPA by human CYP1B1 and mouse Cyp1b1 was confirmed in vitro. 8,9-EET and 19,20-EpDPA selectively and dose-dependently sensitized and activated TRPA1 in overexpressing HEK-293 cells and Trpa1-expressing/AITC-responsive cultured mouse peptigergic DRG neurons. Activation of TRPA1 was attenuated by the antagonist A967079, and mouse Trpa1 was more responsive to agonists including 8,9-EET and 19,20-EpDPA than human TRPA1. This latter effect was mediated in part by amino acids Y933, G939, and S921. Intra-plantar injection of 19,20-EpDPA induced acute mechanical, but not thermal hypersensitivity in mice, which was blocked by A967079. Similarly, Cyp1b1 knockout mice displayed a reduced chronic pain phenotype, indicating a role for Cyp1b1-derived oxylipins in promoting Trpa1 activation and pain. Manipulation of the CYP1B1-oxylipin-TRPA1 axis following nerve injury could have therapeutic benefit.

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Vitamin C and L-Proline antagonistic effects capture alternative states in the pluripotency continuum [RRBS]

Project description:RRBS analysis identified ~1000 differentially methylated regions (DMRs), distributed throughout all chromosomes Interestingly, the majority of DMRs (77% at day 2 and 96% at day 5) that were hypomethylated in VitC-, were conversely hypermethylated in L-Pro-treated ESCs, thus indicating that VitC and L-Pro modulate methylation at the same DNA regions in an opposite manner. Of note, a high fraction of DMRs (50%) laid in promoters (mostly HCPs) and ~20% in enhancers. Moreover, DMRs-associated genes are highly enriched in genes related to developmental process (p=6,3E-38) and DNA-binding transcriptional regulators (p=9,7E-34). Our findings provide the first evidence that L-Pro availability regulates DNA methylation in ESCs and leads to the hypothesis that the antagonistic effects of VitC and L-Pro on DNA methylation pattern might regulate pluripotency.

2017-02-03 | GSE84372 | GEO

RNA-seq raw data and analysis for APP, Shal495 and TrpA1 Drosophila melanogaster mutants

Project description:Evidence suggests that impaired synaptic and firing homeostasis represents a driving force of early Alzheimer’s disease (AD) progression. Here, we examine synaptic and sleep homeostasis in a Drosophila model by overexpressing human amyloid precursor protein (APP), whose duplication and mutations cause familial early-onset AD. We find that APP overexpression induces synaptic hyperexcitability. RNA-seq data indicate exaggerated expression of Ca2+ related signaling genes in APP mutants, including genes encoding Dmca1D, calcineurin (CaN) complex, and IP3R, but not in hyperexcitable mutants caused by TrpA1 or Shal/Kv4. We further demonstrate that increased CaN activity triggers transcriptional activation of Itpr (IP3R) through activating nuclear factor of activated T cells (NFAT). Strikingly, APP overexpression causes defects in both synaptic downscaling and sleep deprivation induced sleep rebound, and both defects could be restored by inhibiting IP3R. Our findings uncover IP3R as a shared signaling molecular in synaptic downscaling and sleep homeostasis, and its dysregulation may lead to synaptic hyperexcitability and AD progression at early stage.

2022-02-18 | GSE196770 | GEO

Genome-wide characterization of DNMT-deficient mouse ESCs reveals dynamicity of differentially-methylated-regions and its impact on bivalency composition

Project description:Differentially-methylated-regions (DMRs), pivotal to the diagnosis/pathogenesis of imprinting disorders, control imprinted gene expression with histone modifications; however, their establishment, numbers, boundaries, and crosstalk with chromatin remain elusive. Herein our global profiling reveals that although de novo methyltransferases DNMT3a/3b are required for locus-specific DMR maintenance, DNMT1 is required for all known DMRs. Based on the latter and the DMR concept, we have developed two novel approaches, “no restored DMRs (NORED)” and “Tag-mosaicity,” to identify/demarcate 31 known and 7 novel DMRs from 21 known loci, and 20 novel DMRs from novel loci. Tag-mosaicity analyses reveal the expected bimodal patterns of hypo/hypermethylated tags of known and new DMRs. Using Gtl2 locus, we demonstrate that methylation of DMRs controls H3K9me3 distribution to a long- range ”DMR-territory” that extends beyond our defined DMR boundary. These findings contrast that H3K9me3 controls CG methylation in Arabidopsis and Neurospora. Our analyses reveal that promoters of imprinted genes within a DMR-territory tend to have H3K4me2 and H3K9me3 with/without H3K27me3, whereas promoters outside have H3K27me3 and H3K4me2. Lastly, we confirmed that the transient DMR of Hcn2/Polrmt locus is conserved in the human genome. Our data link transient DMRs to epilepsy and chronic pain, Parkinson’s disease, Charcot-Marie-Tooth disease, and type 2 diabetes.

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