DNA methylation of human endogenous retrovirus in systemic lupus erythematosus : Journal of Human Genetics

Previous studies have reported that T cells from active systemic lupus erythematosus (SLE) patients contained global hypomethylation and demethylation at the promoter of several genes, which may contribute to the pathogenesis of the disease. Currently there are scarce data on methylation of retroelements in patients with SLE. We estimated and compared the methylated levels of human endogenous retroviruses (HERV)-E and HERV-K in normal and SLE CD3+CD4+ T lymphocytes, CD8+ T and B lymphocytes by using combined bisulfite restriction analysis-interspersed repetitive sequences (COBRA-IRS). HERV-E LTR2C methylation level in CD3+CD4+ T lymphocytes of active SLE was significantly lower than inactive SLE and normal controls (P=0.023 and 0.035, respectively). Surprisingly, HERV-K LTR5_Hs hypomethylation was significantly detected in CD3+CD4+ T lymphocytes from patients with inactive SLE when compared with the active SLE and normal controls (P=0.027 and 0.002, respectively). Demethylation of HERV-K LTR5_Hs in B cells was also detected when compared with the normal controls (P=0.048). Furthermore, the hypomethylation of HERV-E LTR2C in CD3+CD4+ T lymphocytes was positively correlated with lymphopenia in active SLE, whereas the hypomethylation of HERV-K LTR5_Hs was significantly correlated with complement activity and Systemic Lupus Erythematosus Disease Activity Index score. In summary, for each lymphocyte subset in patients with SLE, IRS hypomethylation was found to be type specific. Further studies are needed to confirm and explain these observations.

(Thanks Daniel)

Distinctive patterns of DNA methylation associated with Parkinson disease: Identification of concordant epigenetic changes in brain and peripheral blood leukocytes.

 Parkinson disease (PD) is a multifactorial neurodegenerative disorder with high incidence in the elderly, where environmental and genetic factors are involved in etiology. In addition, epigenetic mechanisms, including deregulation of DNA methylation have been recently associated to PD. As accurate diagnosis cannot be achieved pre-mortem, identification of early pathological changes is crucial to enable therapeutic interventions before major neuropathological damage occurs. Here we investigated genome-wide DNA methylation in brain and blood samples from PD patients and observed a distinctive pattern of methylation involving many genes previously associated to PD, therefore supporting the role of epigenetic alterations as a molecular mechanism in neurodegeneration. Importantly, we identified concordant methylation alterations in brain and blood, suggesting that blood might hold promise as a surrogate for brain tissue to detect DNA methylation in PD and as a source for biomarker discovery.

Molecular Psychiatry - Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits

Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.

Stress May Cause Illness By Methylating Genes: MNT

The researchers invited 76 participants in their sixties to undergo two types of stressful event: one was to to take part in a mock job interview, and the other was to solve arithmetic problems under observation. Both these tests are commonly used to produce stress under lab conditions.The participants gave blood samples before the tests, and also twice afterwards: one ten minutes after (post-test), and another 1.5 hours after (follow-up). From these the researchers could measure the amount of DNA methylation in the two genes.They found that the BDNF gene remained unaffected by any of the stress tests.But the OXTR gene showed methylation changes. There was an increase in methylation in a section of the OXTR gene in the post-test measure: this suggests the cells formed fewer receptors.

The APP family members are key players in S-adenosylmethionine formation by MAT2A and modify BACE1 and PSEN1 gene expression - relevance for Alzheimer`s disease.

A central hallmark of Alzheimers disease (AD) are senile plaques mainly composed of [beta] amyloid, which is a cleavage product of the amyloid precursor protein (APP). The physiological function of APP and its family members APLP1 and APLP2 is poorly understood. In order to fill this gap, we established a cell-culture based model with simultaneous knockdown of all members of the family. A comprehensive proteome study of the APP/APLP1/APLP2 knockdown cell lysates vs. controls revealed significant protein abundance changes of more than 30 proteins. Targeted validation of selected candidates by immunoblotting supported the significant down-regulation of the methionine adenosyltransferase II, alpha (MAT2A) as well as of peroxiredoxin 4 (PRDX4) in the knockdown cells. Moreover, MAT2A was significantly down-regulated at the mRNA level as well. MAT2A catalyzes the production of S-adenosylmethionine (SAM) from methionine and ATP, which plays a pivotal role in the methylation of neurotransmitters, DNA, proteins, and lipids. MAT2A-dependent significant up-regulation of SAM was also detectable in the knockdown cells compared to controls. Our results point to a role of the APP family proteins in cellular methylation mechanisms and fit to findings of disturbed SAM levels in tissue and CSF of Alzheimer disease patients vs. controls. Importantly, methylation plays a central role for neurotransmitter generation like acetylcholine pointing to a crucial relevance of our findings for AD. In addition, we identified differential gene expression of BACE1 and PSEN1 in the knockdown cells, which is possibly a consequence of MAT2A deregulation and may indicate a self regulatory mechanism.

Widespread dynamic DNA methylation in response to biotic stress

Regulation of gene expression by DNA methylation is crucial for defining cellular identities and coordinating organism-wide developmental programs in many organisms. In plants, modulation of DNA methylation in response to environmental conditions represents a potentially robust mechanism to regulate gene expression networks; however, examples of dynamic DNA methylation are largely limited to gene imprinting. Here we report an unexpected role for DNA methylation in regulation of the Arabidopsis thaliana immune system. Profiling the DNA methylomes of plants exposed to bacterial pathogen, avirulent bacteria, or salicylic acid (SA) hormone revealed numerous stress-induced differentially methylated regions, many of which were intimately associated with differentially expressed genes. In response to SA, transposon-associated differentially methylated regions, which were accompanied by up-regulation of 21-nt siRNAs, were often coupled to transcriptional changes of the transposon and/or the proximal gene. Thus, dynamic DNA methylation changes within repetitive sequences or transposons can regulate neighboring genes in response to SA stress.

Futurity.org – Test detects cancer from immune cell mix

A new blood test determines the relative abundance of leukocytes, immune cells that can indicate cancer and other disorders.The key to the new technique is that scientists have identified in each kind of leukocyte a unique DNA methylation signature.

Human cytomegalovirus infection is sensitive to the host cell DNA methylation state and alters global DNA methylation capacity.

Epigenetics and gene methylation play an important role in many disorders. This study showed that cytomegalovirus infection has marked effect on host gene methylation. How many other viruses produce similar effects ?
Abstract:
Human Cytomegalovirus (HCMV) is a ubiquitous herpesvirus that infects and establishes latency in the majority of the human population and may cause fatal infections in immunocompromised patients. Recent data implies a close interaction between HCMV encoded proteins and cellular epigenetic mechanisms such as histone acetylation and deacetylation. In this study, we investigated the interactions between HCMV infection and the DNA methylation machinery in different host cells using several approaches. We found that colon cancer cell line HCT-116 lacking the DNMT1 and DNMT3b methyltransferases was susceptible to HCMV-AD169 infection, while wild-type cells were non-susceptible. Treatment of wild-type HCT-116 cells with 5-azacytidine rendered them susceptible to infection. Further investigation of HCMV infected MRC-5 fibroblasts demonstrated significant global hypomethylation, a phenomenon that was virus strain-specific and associated with the re-localization of DNMT1 and DNMT3b from the nucleus to the cytoplasm. The cytoplasmic accumulation of DNMT1 was also evident in in vitro infected macrophages and in epithelial cells in tissue samples from patients with inflammatory bowel disease and concomitant HCMV infection. Foscavir treatment of virus infected fibroblasts did not affect the majority of the virus induced nuclear exclusion of DNMT1, which suggest that it is dependent on viral IE gene products. In conclusion, HCMV infection results in profound effects on the host cell DNA methylation machinery and is associated with inflammation in vivo. Our results improve the understanding of cytomegalovirus pathogenesis and open the search for new antiviral therapy targets. These findings may also contribute to the further understanding of mechanisms involved in DNA methylation abnormalities in physiological and pathological conditions.