Publications by authors named "Sara Gombert"

6 Publications

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Correction to: Transient receptor potential ankyrin 1 promoter methylation and peripheral pain sensitivity in Crohn's disease.

Clin Epigenetics 2021 Mar 30;13(1):67. Epub 2021 Mar 30.

Laboratory for Molecular Neuroscience, Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Feodor-Lynen-Str. 35, 30625, Hannover, Germany.

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http://dx.doi.org/10.1186/s13148-021-01059-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011209PMC
March 2021

Transient receptor potential ankyrin 1 promoter methylation and peripheral pain sensitivity in Crohn's disease.

Clin Epigenetics 2019 12 31;12(1). Epub 2019 Dec 31.

Laboratory for Molecular Neuroscience, Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Feodor-Lynen-Str. 35, 30625, Hannover, Germany.

Background: Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract associated with abdominal pain and diarrhea. Pain caused by Crohn's disease likely involves neurogenic inflammation which seems to involve the ion channel transient receptor potential ankyrin 1 (TRPA1). Since the promoter methylation of TRPA1 was shown to influence pain sensitivity, we asked if the expression of TRPA1 is dysregulated in patients suffering from Crohn's disease. The methylation rates of CpG dinucleotides in the TRPA1 promoter region were determined from DNA derived from whole blood samples of Crohn patients and healthy participants. Quantitative sensory testing was used to examine pain sensitivities.

Results: Pressure pain thresholds were lower in Crohn patients as compared to healthy participants, and they were also lower in females than in males. They correlated inversely with the methylation rate at the CpG - 628 site of the TRPA1 promoter. This effect was more pronounced in female compared to male Crohn patients. Similar results were found for mechanical pain thresholds. Furthermore, age-dependent effects were detected. Whereas the CpG - 628 methylation rate declined with age in healthy participants, the methylation rate in Crohn patients increased. Pressure pain thresholds increased with age in both cohorts.

Conclusions: The TRPA1 promoter methylation appears to be dysregulated in patients suffering from Crohn's disease, and this effect is most obvious when taking gender and age into account. As TRPA1 is regarded to be involved in pain caused by neurogenic inflammation, its aberrant expression may contribute to typical symptoms of Crohn's disease.
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http://dx.doi.org/10.1186/s13148-019-0796-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938615PMC
December 2019

Childhood traumatization is associated with differences in TRPA1 promoter methylation in female patients with multisomatoform disorder with pain as the leading bodily symptom.

Clin Epigenetics 2019 08 28;11(1):126. Epub 2019 Aug 28.

Department of Anesthesiology and Intensive Care Medicine, Pain Clinic, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Background: The construct of multisomatoform disorder (MSD) is a common point of reference for patients in different somatic and psychosomatic specialties and therefore useful in studying large well-characterized cohorts of a prototype of a somatoform disorder and in parallel as a functional somatic syndrome (FSS). This disorder is characterized by distressing and functionally disabling somatic symptoms with chronic pain as the most frequent and clinically relevant complaint. Pain is perceived by nociceptive nerve fibers and transferred through the generation of action potentials by different receptor molecules known to determine pain sensitivity in pathophysiological processes. Previous studies have shown that for the transient receptor potential ankyrin 1 (TRPA1), receptor methylation of a particular CpG dinucleotide in the promoter region is inversely associated with both heat pain and pressure pain thresholds. In this study, we hypothesized that TRPA1 promoter methylation regulates pain sensitivity of patients with multisomatoform disorder (MSD). A cohort of 151 patients with MSD and 149 matched healthy volunteers were evaluated using quantitative sensory testing, clinical and psychometric assessment, and methylation analysis using DNA isolated from whole blood.

Results: We found CpG -628 to be correlated with mechanical pain threshold and CpG -411 to be correlated with mechanical pain threshold in female volunteers, i.e., higher methylation levels lead to higher pain thresholds. A novel finding is that methylation levels were significantly different between patients with no and severe levels of childhood trauma. CpG methylation also correlated with psychometric assessment of pain and pain levels rated on a visual analog scale.

Conclusion: Our findings support the hypothesis that epigenetic regulation of TRPA1 plays a role in mechanical pain sensitivities in healthy volunteers. They further provide evidence for the possible influence of childhood traumatic experiences on the epigenetic regulation of TRPA1 in patients with MSD.
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http://dx.doi.org/10.1186/s13148-019-0731-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712620PMC
August 2019

Epigenetic divergence in the TRPA1 promoter correlates with pressure pain thresholds in healthy individuals.

Pain 2017 04;158(4):698-704

Laboratory for Molecular Neuroscience, Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.

The expression pattern of important transduction molecules in nociceptive sensory neurons is likely to dictate pain sensitivity. While this notion is well established for increased pain sensitivities under conditions like inflammation and neuropathy, less is known as to which molecules are defining interindividual differences in pain sensitivity in healthy subjects. A genome-wide methylation analysis on monozygotic twins found that methylation of a CpG dinucleotide in the promoter of transient receptor potential ankyrin 1 (TRPA1) is inversely associated with the threshold for heat-induced pain. Several in vitro studies also suggest that TRPA1 mediates mechanical sensitivity of sensory afferents, thus potentially mediating pressure-evoked pain. In the present study, we therefore investigated the epigenetic predisposition for pressure pain by analyzing the methylation status of 47 CpG sites in the promoter region of TRPA1. Using DNA from whole-blood samples of 75 healthy volunteers, we found that the same CpG site previously found to affect the threshold for heat-evoked pain is hypermethylated in subjects with a low threshold for pressure pain. We also found gender differences, with females displaying higher methylation rates combined with higher pressure pain sensitivities as compared with males. In conclusion, our findings support the notion that epigenetic regulation of TRPA1 seems to regulate thermal and mechanical pain sensitivities.
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http://dx.doi.org/10.1097/j.pain.0000000000000815DOI Listing
April 2017

Telomere dynamics and homeostasis in a transmissible cancer.

PLoS One 2012 29;7(8):e44085. Epub 2012 Aug 29.

Faculty of Veterinary Sciences, University of Sydney, Sydney, Australia.

Background: Devil Facial Tumour Disease (DFTD) is a unique clonal cancer that threatens the world's largest carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii) with extinction. This transmissible cancer is passed between individual devils by cell implantation during social interactions. The tumour arose in a Schwann cell of a single devil over 15 years ago and since then has expanded clonally, without showing signs of replicative senescence; in stark contrast to a somatic cell that displays a finite capacity for replication, known as the "Hayflick limit".

Methodology/principal Findings: In the present study we investigate the role of telomere length, measured as Telomere Copy Number (TCN), and telomerase and shelterin gene expression, as well as telomerase activity in maintaining hyperproliferation of Devil Facial Tumour (DFT) cells. Our results show that DFT cells have short telomeres. DFTD TCN does not differ between geographic regions or between strains. However, TCN has increased over time. Unlimited cell proliferation is likely to have been achieved through the observed up-regulation of the catalytic subunit of telomerase (TERT) and concomitant activation of telomerase. Up-regulation of the central component of shelterin, the TRF1-intercating nuclear factor 2 (TINF2) provides DFT a mechanism for telomere length homeostasis. The higher expression of both TERT and TINF2 may also protect DFT cells from genomic instability and enhance tumour proliferation.

Conclusions/significance: DFT cells appear to monitor and regulate the length of individual telomeres: i.e. shorter telomeres are elongated by up-regulation of telomerase-related genes; longer telomeres are protected from further elongation by members of the shelterin complex, which may explain the lack of spatial and strain variation in DFT telomere copy number. The observed longitudinal increase in gene expression in DFT tissue samples and telomerase activity in DFT cell lines might indicate a selection for more stable tumours with higher proliferative potential.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044085PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430654PMC
February 2013

Proteomics and deep sequencing comparison of seasonally active venom glands in the platypus reveals novel venom peptides and distinct expression profiles.

Mol Cell Proteomics 2012 Nov 16;11(11):1354-64. Epub 2012 Aug 16.

Faculty of Veterinary Science, The University of Sydney, Camperdown, NSW 2006, Australia.

The platypus is a venomous monotreme. Male platypuses possess a spur on their hind legs that is connected to glands in the pelvic region. They produce venom only during the breeding season, presumably to fight off conspecifics. We have taken advantage of this unique seasonal production of venom to compare the transcriptomes of in- and out-of-season venom glands, in conjunction with proteomic analysis, to identify previously undiscovered venom genes. Comparison of the venom glands revealed distinct gene expression profiles that are consistent with changes in venom gland morphology and venom volumes in and out of the breeding season. Venom proteins were identified through shot-gun sequenced venom proteomes of three animals using RNA-seq-derived transcripts for peptide-spectral matching. 5,157 genes were expressed in the venom glands, 1,821 genes were up-regulated in the in-season gland, and 10 proteins were identified in the venom. New classes of platypus-venom proteins identified included antimicrobials, amide oxidase, serpin protease inhibitor, proteins associated with the mammalian stress response pathway, cytokines, and other immune molecules. Five putative toxins have only been identified in platypus venom: growth differentiation factor 15, nucleobindin-2, CD55, a CXC-chemokine, and corticotropin-releasing factor-binding protein. These novel venom proteins have potential biomedical and therapeutic applications and provide insights into venom evolution.
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http://dx.doi.org/10.1074/mcp.M112.017491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494181PMC
November 2012
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