Tag: methylation

Acute psychosocial stress-mediated changes in the expression and methylation of perforin in chronic fatigue syndrome

Abstract:

Perforin (PRF1) is essential for immune surveillance and studies report decreased perforin in chronic fatigue syndrome (CFS), an illness potentially associated with stress and/or infection. We hypothesize that stress can influence regulation of PRF1 expression, and that this regulation will differ between CFS and non-fatigued (NF) controls.

We used the Trier Social Stress Test (TSST) as a standardized acute psychosocial stress, and evaluated its effect on PRF1 expression and methylation in CFS (n = 34) compared with NF (n = 47) participants. During the TSST, natural killer (NK) cells increased significantly in both CFS (P = <0.0001) and NF subjects (P = <0.0001). Unlike previous reports, there was no significant difference in PRF1 expression at baseline or during TSST between CFS and NF. However, whole blood PRF1 expression increased 1.6 fold during the TSST in both CFS (P = 0.0003) and NF (P = <0.0001). Further, the peak response immediately following the TSST was lower in CFS compared with NF (P = 0.04).

In addition, at 1.5 hours post TSST, PRF1 expression was elevated in CFS compared with NF (whole blood, P = 0.06; PBMC, P = 0.02). Methylation of seven CpG sites in the methylation sensitive region of the PRF1 promoter ranged from 38%-79% with no significant differences between CFS and NF. Although, the average baseline methylation of all seven CpG sites did not differ between CFS and NF groups, it showed a significant negative correlation with PRF1 expression at all TSST time points in both CFS (r = -0.56, P = <0.0001) and NF (r = -0.38, P = <0.0001). Among participants with high average methylation (≥65%), PRF1 expression was significantly lower in CFS than NF subjects immediately following TSST.

These findings suggest methylation could be an important epigenetic determinant of inter-individual differences in PRF1 expression and that the differences in PRF1 expression and methylation between CFS and NF in the acute stress response require further investigation.

 

Source: Falkenberg VR, Whistler T, Murray JR, Unger ER, Rajeevan MS. Acute psychosocial stress-mediated changes in the expression and methylation of perforin in chronic fatigue syndrome. Genet Epigenet. 2013 Jan 28;5:1-9. doi: 10.4137/GEG.S10944. ECollection 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222335/ (Full article)

 

Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association

Abstract:

Serotonergic neurotransmission plays a key role in the pathophysiology of neuropsychiatric illnesses. The functional significance of a promoter polymorphism, -1438G/A (rs6311), in one of the major genes of this system (serotonin receptor 2A, HTR2A) remains poorly understood in the context of epigenetic factors, transcription factors and endocrine influences. We used functional and structural equation modeling (SEM) approaches to assess the contributions of the polymorphism (rs6311), DNA methylation and clinical variables to HTR2A expression in chronic fatigue syndrome (CFS) subjects from a population-based study. HTR2A was up-regulated in CFS through allele-specific expression modulated by transcription factors at critical sites in its promoter: an E47 binding site at position -1,438, (created by the A-allele of rs6311 polymorphism), a glucocorticoid receptor (GR) binding site encompassing a CpG at position -1,420, and Sp1 binding at CpG methylation site -1,224. Methylation at -1,420 was strongly correlated with methylation at -1,439, a CpG site that is dependent upon the G-allele of rs6311 at position -1,438. SEM revealed a strong negative interaction between E47 and GR binding (in conjunction with cortisol level) on HTR2A expression. This study suggests that the promoter polymorphism (rs6311) can affect both transcription factor binding and promoter methylation, and this along with an individual’s stress response can impact the rate of HTR2A transcription in a genotype and methylation-dependent manner. This study can serve as an example for deciphering the molecular determinants of transcriptional regulation of major genes of medical importance by integrating functional genomics and SEM approaches. Confirmation in an independent study population is required.

 

Source: Falkenberg VR, Gurbaxani BM, Unger ER, Rajeevan MS. Functional genomics of serotonin receptor 2A (HTR2A): interaction of polymorphism, methylation, expression and disease association. Neuromolecular Med. 2011 Mar;13(1):66-76. doi: 10.1007/s12017-010-8138-2. Epub 2010 Oct 13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044825/ (Full article)

 

Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome

Abstract:

Twelve outpatients, all women, who fulfilled the criteria for both fibromyalgia and chronic fatigue syndrome were rated on 15 items of the Comprehensive Psychopathological Rating Scale (CPRS-15). These items were chosen to constitute a proper neurasthenic subscale.

Blood laboratory levels were generally normal. The most obvious finding was that, in all the patients, the homocysteine (HCY) levels were increased in the cerebrospinal fluid (CSF). There was a significant positive correlation between CSF-HCY levels and fatiguability, and the levels of CSF-B12 correlated significantly with the item of fatiguability and with CPRS-15.

The correlations between vitamin B12 and clinical variables of the CPRS-scale in this study indicate that low CSF-B12 values are of clinical importance. Vitamin B12 deficiency causes a deficient remethylation of HCY and is therefore probably contributing to the increased homocysteine levels found in our patient group.

We conclude that increased homocysteine levels in the central nervous system characterize patients fulfilling the criteria for both fibromyalgia and chronic fatigue syndrome.

 

Source: Regland B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE, Gottfries CG. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol. 1997;26(4):301-7. http://www.ncbi.nlm.nih.gov/pubmed/9310111