scholarly journals Paranoid schizophrenia and methamphetamine-induced paranoia are both characterized by a similar LINE-1 partial methylation profile, which is more pronounced in paranoid schizophrenia

2018 ◽  
Author(s):  
Rasmon Kalayasiri ◽  
Korakot Kraijak ◽  
Apiwat Mutirangura ◽  
Michael Maes
Keyword(s):  
Mononuclear Cells ◽  
Restriction Analysis ◽  
Paranoid Schizophrenia ◽  
Strong Association ◽  
Methylation Pattern ◽  
Peripheral Blood Mononuclear ◽  
Immune Disorder ◽  
Global Methylation ◽  
Partial Methylation ◽  
Methylation Patterns

AbstractBackgroundThere is evidence that schizophrenia is a neuro-immune disorder. Genes linked to intragenic LINE-1 methylation show a strong association with immune-associated disorders including psychosis. The aim of this study was to examine LINE-1 methylation patterns in paranoid schizophrenia and methamphetamine-induced paranoia, a model for schizophrenia.MethodsThis study recruited 31 patients with paranoid schizophrenia, 94 with methamphetamine-induced paranoia (MIP) and 163 normal controls. LINE-1 methylation patterns were assayed in peripheral blood mononuclear cells and a combined bisulphite restriction analysis and COBRA were used to estimate global methylation (mC) and LINE-1 CpG dinucleotide methylation patterns, namely 2 methylated (mCmC) and 2 unmethylated (uCuC) CpGs and the partially methylated loci mCuC (5’m with 3’u) and uCmC (5’u with 3’m).ResultsPatients with paranoid schizophrenia show highly significant changes in LINE-1 partial methylation patterns, namely a higher % mCuC and lower % uCmC as compared with controls and MIP patients, while the latter show higher % mCuC but lower % uCmC as compared with controls. Higher % mCuC significantly predicts paranoid schizophrenia with a sensitivity of 51.6%, specificity of 97.5% and an area under the ROC curve of 0.895.ConclusionsThe results indicate that a common dysfunction in LINE-1 partial methylation may underpin both paranoid schizophrenia and MIP and that this methylation pattern is significantly more expressed in paranoid schizophrenia than MIP. Reciprocal links between impairments in LINE-1 methylation and neuro-immune and neuro-oxidative pathways may underpin the pathophysiology of both MIP and paranoid schizophrenia.

Examination of the dynamics of global DNA methylation pattern establishment during spermatogenesiss

2007 ◽  
Vol 30 (4) ◽  
pp. 90
Author(s):  
Kirsten Niles ◽  
Sophie La Salle ◽  
Christopher Oakes ◽  
Jacquetta Trasler
Keyword(s):  
Dna Methylation ◽  
Germ Cell ◽  
Germ Cells ◽  
Epigenetic Modification ◽  
Methylation Pattern ◽  
Chromosome 9 ◽  
Specific Gene ◽  
Global Methylation ◽  
Dna Methylation Pattern ◽  
Methylation Patterns

Background: DNA methylation is an epigenetic modification involved in gene expression, genome stability, and genomic imprinting. In the male, methylation patterns are initially erased in primordial germ cells (PGCs) as they enter the gonadal ridge; methylation patterns are then acquired on CpG dinucleotides during gametogenesis. Correct pattern establishment is essential for normal spermatogenesis. To date, the characterization and timing of methylation pattern acquisition in PGCs has been described using a limited number of specific gene loci. This study aimed to describe DNA methylation pattern establishment dynamics during male gametogenesis through global methylation profiling techniques in a mouse model. Methods: Using a chromosome based approach, primers were designed for 24 regions spanning chromosome 9; intergenic, non-repeat, non-CpG island sequences were chosen for study based on previous evidence that these types of sequences are targets for testis-specific methylation events. The percent methylation was determined in each region by quantitative analysis of DNA methylation using real-time PCR (qAMP). The germ cell-specific pattern was determined by comparing methylation between spermatozoa and liver. To examine methylation in developing germ cells, spermatogonia from 2 day- and 6 day-old Oct4-GFP (green fluorescent protein) mice were isolated using fluorescence activated cell sorting. Results: As compared to liver, four loci were hypomethylated and five loci were hypermethylated in spermatozoa, supporting previous results indicating a unique methylation pattern in male germ cells. Only one region was hypomethylated and no regions were hypermethylated in day 6 spermatogonia as compared to mature spermatozoa, signifying that the bulk of DNA methylation is established prior to type A spermatogonia. The methylation in day 2 spermatogonia, germ cells that are just commencing mitosis, revealed differences of 15-20% compared to day 6 spermatogonia at five regions indicating that the most crucial phase of DNA methylation acquisition occurs prenatally. Conclusion: Together, these studies provide further evidence that germ cell methylation patterns differ from those in somatic tissues and suggest that much of methylation at intergenic sites is acquired during prenatal germ cell development. (Supported by CIHR)

Distinctive patterns of age-dependent hypomethylation in interspersed repetitive sequences

2010 ◽  
Vol 41 (2) ◽  
pp. 194-200 ◽  
Author(s):  
Pornrutsami Jintaridth ◽  
Apiwat Mutirangura
Keyword(s):  
Mononuclear Cells ◽  
Repetitive Sequences ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Cellular Functions ◽  
Peripheral Blood Mononuclear ◽  
Global Methylation ◽  
Short Interspersed Elements ◽  
Genome Wide ◽  
Age Dependent

Interspersed repetitive sequences (IRSs) are a major contributor to genome size and may contribute to cellular functions. IRSs are subdivided according to size and functionally related structures into short interspersed elements, long interspersed elements (LINEs), DNA transposons, and LTR-retrotransposons. Many IRSs may produce RNA and regulate genes by a variety of mechanisms. The majority of DNA methylation occurs in IRSs and is believed to suppress IRS activities. Global hypomethylation, or the loss of genome-wide methylation, is a common epigenetic event not only in senescent cells but also in cancer cells. Loss of LINE-1 methylation has been characterized in many cancers. Here, we evaluated the methylation levels of peripheral blood mononuclear cells of LINE-1, Alu, and human endogenous retrovirus K (HERV-K) in 177 samples obtained from volunteers between 20 and 88 yr of age. Age was negatively associated with methylation levels of Alu (r = −0.452, P < 10−3) and HERV-K (r = −0.326, P < 10−3) but not LINE-1 (r = 0.145, P = 0.055). Loss of methylation of Alu occurred during ages 34–68 yr, and loss of methylation of HERV-K occurred during ages 40–63 yr and again during ages 64–83 yr. Interestingly, methylation of Alu and LINE-1 are directly associated, particularly at ages 49 yr and older (r = 0.49, P < 10−3). Therefore, only some types of IRSs lose methylation at certain ages. Moreover, Alu and HERV-K become hypomethylated differently. Finally, there may be several mechanisms of global methylation. However, not all of these mechanisms are age-dependent. This finding may lead to a better understanding of not only the biological causes and consequences of genome-wide hypomethylation but also the role of IRSs in the aging process.

scholarly journals An open-label, phase II multicohort study of an oral hypomethylating agent CC-486 and durvalumab in advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e000883
Author(s):  
Kirsty Taylor ◽  
Helen Loo Yau ◽  
Ankur Chakravarthy ◽  
Ben Wang ◽  
Shu Yi Shen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mononuclear Cells ◽  
Dna Demethylation ◽  
Lessons Learned ◽  
Clinical Activity ◽  
Open Label ◽  
Peripheral Blood Mononuclear ◽  
Global Methylation ◽  
Hypomethylating Agent ◽  
Tumor Biopsies

PurposeTo evaluate whether administration of the oral DNA hypomethylating agent CC-486 enhances the poor response rate of immunologically ‘cold’ solid tumors to immune checkpoint inhibitor durvalumab.Experimental designPD-L1/PD-1 inhibitor naïve patients with advanced microsatellite stable colorectal cancer; platinum resistant ovarian cancer; and estrogen receptor positive, HER2 negative breast cancer were enrolled in this single-institution, investigator-initiated trial. Two 28 day regimens, regimen A (CC-486 300 mg QD Days 1–14 (cycles 1–3 only) in combination with durvalumab 1500 mg intravenous day 15) and regimen B (CC-486 100 mg QD days 1–21 (cycle 1 and beyond), vitamin C 500 mg once a day continuously and durvalumab 1500 mg intravenous day 15) were investigated. Patients underwent paired tumor biopsies and serial peripheral blood mononuclear cells (PBMCs) collection for immune-profiling, transcriptomic and epigenomic analyzes.ResultsA total of 28 patients were enrolled, 19 patients treated on regimen A and 9 on regimen B. The combination of CC-486 and durvalumab was tolerable. Regimen B, with a lower dose of CC-486 extended over a longer treatment course, showed less grade 3/4 adverse effects. Global LINE-1 methylation assessment of serial PBMCs and genome-wide DNA methylation profile in paired tumor biopsies demonstrated minimal changes in global methylation in both regimens. The lack of robust tumor DNA demethylation was accompanied by an absence of the expected ‘viral mimicry’ inflammatory response, and consequently, no clinical responses were observed. The disease control rate was 7.1%. The median progression-free survival was 1.9 months (95% CI 1.5 to 2.3) and median overall survival was 5 months (95% CI 4.5 to 10).ConclusionsThe evaluated treatment schedules of CC-486 in combination with durvalumab did not demonstrate robust pharmacodynamic or clinical activity in selected immunologically cold solid tumors. Lessons learned from this biomarker-rich study should inform continued drug development efforts using these agents.Trial registration numberNCT02811497.

scholarly journals Methylation Status of Alu and LINE-1 Interspersed Repetitive Sequences in Behcet’s Disease Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Şahru Yüksel ◽  
Selma Ozbek Kucukazman ◽  
Gülten Sungur Karataş ◽  
Mehmet Akif Ozturk ◽  
Sasiprapa Prombhul ◽  
...  
Keyword(s):  
Behçet’S Disease ◽  
Behcet’S Disease ◽  
Mononuclear Cells ◽  
Behçet's Disease ◽  
Restriction Analysis ◽  
Methylation Status ◽  
Repetitive Sequences ◽  
Ocular Involvement ◽  
Partial Methylation ◽  
Behcet's Disease

Behcet’s Disease (BD) is a multisystem chronic inflammatory disease. The pathology is believed to involve both genetic susceptibility and environmental factors. Hypomethylation leading to activation of interspersed repetitive sequences (IRSs) such as LINE-1 and Alu contributes to the pathologies of autoimmune diseases and cancer. Herein, the epigenetic changes of IRSs in BD were evaluated using combined bisulfite restriction analysis-interspersed repetitive sequences (COBRA-IRS). DNA from neutrophils and peripheral blood mononuclear cells (PBMCs) of BD patients with ocular involvement that were in active or inactive states and healthy controls were used to analyze LINE-1 and Alu methylation levels. For Alu sequences, significant differences were observed in the frequency ofCuCualleles between PBMCs of patients and controls (p=0.03), and between inactive patients and controls (p=0.03). For neutrophils, the frequency ofCuCuwas significantly higher between patients and controls (p=0.006) and between inactive patients and controls (p=0.002). The partial methylation (CuCm+CmCu) frequencies of Alu between inactive patients and control samples also differed (p=0.02). No statistically significant differences for LINE-1 were detected. Thus, changes in the methylation level of IRS elements might contribute to the pathogenesis of BD. The role of Alu transcripts in BD should be investigated further.

scholarly journals Identification and Antigenicity of Broadly Cross-Reactive and Conserved Human Immunodeficiency Virus Type 1-Derived Helper T-Lymphocyte Epitopes

2001 ◽  
Vol 75 (9) ◽  
pp. 4195-4207 ◽  
Author(s):  
Cara C. Wilson ◽  
Brent Palmer ◽  
Scott Southwood ◽  
John Sidney ◽  
Yuichiro Higashimoto ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Strong Association ◽  
Peripheral Blood Mononuclear ◽  
Hla Dr ◽  
Immunodeficiency Virus ◽  
Binding Peptides ◽  
Hiv Type 1 ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus (HIV)-specific helper T lymphocytes (HTL) play a key role in the immune control of HIV type 1 (HIV-1) infection, and as such are an important target of potential HIV-1 vaccines. In order to identify HTL epitopes in HIV-1 that might serve as vaccine targets, conserved HIV-1-derived peptides bearing an HLA-DR binding supermotif were tested for binding to a panel of the most representative HLA-DR molecules. Eleven highly cross-reactive binding peptides were identified: three in Gag and eight in Pol. Lymphoproliferative responses to this panel of peptides, as well as to the HIV-1 p24 and p66 proteins, were evaluated with a cohort of 31 HIV-1-infected patients. All 11 peptides were recognized by peripheral blood mononuclear cells from multiple HIV-infected donors. Many of the responsive HIV-infected subjects showed recognition of multiple peptides, indicating that HIV-1-specific T-helper responses may be broadly directed in certain individuals. A strong association existed between recognition of the parental recombinant HIV-1 protein and the corresponding HTL peptides, suggesting that these peptides represent epitopes that are processed and presented during the course of HIV-1 infection. Lastly, responses to the supermotif peptides were mediated by CD4+ T cells and were restricted by major histocompatibility complex class II molecules. The epitopes described herein are potentially important components of HIV-1 therapeutic and prophylactic vaccines.

Peripheral blood mononuclear cells are hypomethylated in active rheumatoid arthritis and methylation correlates with disease activity

Rheumatology ◽  
2020 ◽  
Author(s):  
Ilka Liebold ◽  
Andreas Grützkau ◽  
Anika Göckeritz ◽  
Velia Gerl ◽  
Randall Lindquist ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Disease Activity ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Global Dna Methylation ◽  
Peripheral Blood Mononuclear ◽  
Global Methylation ◽  
Blood Mononuclear Cells ◽  
Signal Intensities

Abstract Objective Epigenetic modifications are dynamic and influence cellular disease activity. The aim of this study was to investigate global DNA methylation in peripheral blood mononuclear cells (PBMCs) of RA patients to clarify whether global DNA methylation pattern testing might be useful in monitoring disease activity as well as the response to therapeutics. Methods Flow cytometric measurement of 5-methyl-cytosine (5′-mC) was established using the cell line U937. In the subsequent prospective study, 62 blood samples were investigated, including 17 healthy donors and 45 RA patients at baseline and after 3 months of treatment with methotrexate, the IL-6 receptor inhibitor sarilumab, and Janus kinase inhibitors. Methylation status was assessed with an anti-5′-mC antibody and analysed in PBMCs and CD4+, CD8+, CD14+ and CD19+ subsets. Signal intensities of 5′-mC were correlated with 28-joint DASs with ESR and CRP (DAS28-ESR and DAS28-CRP). Results Compared with healthy individuals, PBMCs of RA patients showed a significant global DNA hypomethylation. Signal intensities of 5′-mC correlated with transcription levels of DNMT1, DNMT3B and MTR genes involved in methylation processes. Using flow cytometry, significant good correlations and linear regression values were achieved in RA patients between global methylation levels and DAS28-ESR values for PBMCs (r = −0.55, P = 0.002), lymphocytes (r = −0.57, P = 0.001), CD4+ (r = −0.57, P = 0.001), CD8+ (r = −0.54, P = 0.001), CD14+ (r = −0.49, P = 0.008) and CD19+ (r = −0.52, P = 0.004) cells. Conclusions The degree of global DNA methylation was found to be associated with disease activity. Based on this novel approach, the degree of global methylation is a promising biomarker for therapy monitoring and the prediction of therapy outcome in inflammatory diseases.

scholarly journals LINE-1 Methylation Patterns as a Predictor of Postmolar Gestational Trophoblastic Neoplasia

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Ruangsak Lertkhachonsuk ◽  
Krissada Paiwattananupant ◽  
Patou Tantbirojn ◽  
Prakasit Rattanatanyong ◽  
Apiwat Mutirangura
Keyword(s):  
Hydatidiform Mole ◽  
First Trimester ◽  
Methylation Pattern ◽  
Gestational Trophoblastic Neoplasia ◽  
Partial Methylation ◽  
Clinical Appearance ◽  
Malignant Trophoblast ◽  
Sensitivity Specificity ◽  
Methylation Patterns ◽  
Hydatidiform Moles

Objective. To study the potential of long interspersed element-1 (LINE-1) methylation change in the prediction of postmolar gestational trophoblastic neoplasia (GTN).Methods. The LINE-1 methylation pattern from first trimester placenta, hydatidiform mole, and malignant trophoblast specimens were compared. Then, hydatidiform mole patients from 11999 to 2010 were classified into the following 2 groups: a remission group and a group that developed postmolar GTN. Specimens were prepared for a methylation study. The methylation levels and percentages of LINE-1 loci were evaluated for their sensitivity, specificity, and accuracy for the prediction of postmolar GTN.Results. First, 12 placentas, 38 moles, and 19 malignant trophoblast specimens were compared. The hydatidiform mole group had the highest LINE-1 methylation level (p= 0.003) and theuCuC of LINE-1 increased in the malignant trophoblast group (p≤ 0.001). One hundred forty-five hydatidiform mole patients were classified as 103 remission and 42 postmolar GTN patients. The %mCuC and %uCmC of LINE-1 showed the lowestpvalue for distinguishing between the two groups (p< 0.001). The combination of the pretreatmentβ-hCG level (≥100,000 mIU/mL) with the %mCuC and %uCmC, sensitivity, specificity, PPV, NPV, and accuracy modified the levels to 60.0%, 92.2%, 77.4%, 83.8%, and 82.3%, respectively.Conclusions. A reduction in the partial methylation of LINE-1 occurs early before the clinical appearance of malignant transformation. The %mCuC and %uCmC of LINE-1s may be promising markers for monitoring hydatidiform moles before progression to GTN.

scholarly journals Mild SARS-CoV-2 infection modifies DNA methylation of peripheral blood mononuclear cells from COVID-19 convalescents

2021 ◽  
Author(s):  
Johanna Huoman ◽  
Shumaila Sayyab ◽  
Eirini Apostolou ◽  
Lovisa Karlsson ◽  
Lucas Porcile ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Network Analyses ◽  
Differentially Methylated Genes ◽  
Blood Mononuclear Cells ◽  
Methylation Patterns

Background: Coronaviruses such as SARS-CoV-2 may circumvent host defence mechanisms by hijacking host proteins, possibly by altering DNA methylation patterns in host cells. While most epigenetic studies have been performed in severely ill COVID-19 patients, studies on individuals who have recovered from mild-to-moderate disease remain scarce. The aim of this study was to assess epigenome-wide DNA methylation patterns in COVID-19 convalescents compared to uninfected controls from before and after the pandemic outbreak began. Methods: DNA was extracted from peripheral blood mononuclear cells originating from uninfected controls before (Pre20, n=5) and after (Con, n=18) 2020, COVID-19 convalescents (CC19, n=14) and symptom-free individuals with a SARS-CoV-2-specific T cell response (SFT, n=6), as well as from Pre20 (n=4) samples stimulated in vitro with SARS-CoV-2. Subsequently, epigenome-wide DNA methylation analyses were performed using the Illumina MethylationEPIC 850K array, and statistical and bioinformatic analyses comprised differential DNA methylation, pathway over-representation and module identification network analyses. Results: DNA methylation patterns of COVID-19 convalescents were altered as compared to uninfected controls, with similar results observed in in vitro stimulations of PBMC with SARS-CoV-2. Differentially methylated genes from the in vivo comparison constituted the foundation for the identification of a possibly SARS-CoV-2-induced module, containing 66 genes of which six could also be identified in corresponding analyses of the in vitro data (TP53, INS, HSPA4, SP1, ESR1 and FAS). Pathway over-representation analyses revealed involvement of Wnt, cadherin and apoptosis signalling pathways amongst others. Furthermore, numerous interactions were found between the obtained differentially methylated genes from both settings and the network analyses when overlaying the data unto the SARS-CoV-2 interactome. Conclusions: Epigenome-wide DNA methylation patterns of individuals that have recovered from mild-to-moderate COVID-19 are different from those of non-infected controls. The observed alterations during both in vivo and in vitro exposure to SARS-CoV-2 showed involvement in interactions and pathways that are highly relevant to COVID-19. The present study provides indications that DNA methylation is one of several epigenetic mechanisms that is altered upon SARS-CoV-2 infection. Further studies on the mechanistic underpinnings should determine whether the observed effects are reflecting host-protective antiviral defence or targeted viral hijacking to evade host defence.

scholarly journals DNA Methylation Reprogramming during Mammalian Development

Genes ◽  
2019 ◽  
Vol 10 (4) ◽  
pp. 257 ◽  
Author(s):  
Yang Zeng ◽  
Taiping Chen
Keyword(s):  
Dna Methylation ◽  
Primordial Germ Cells ◽  
Dna Methyltransferases ◽  
Methylation Pattern ◽  
Mammalian Development ◽  
Dynamic Changes ◽  
Global Methylation ◽  
Somatic Tissues ◽  
Methylation Patterns ◽  
Second Wave

DNA methylation (5-methylcytosine, 5mC) is a major form of DNA modification in the mammalian genome that plays critical roles in chromatin structure and gene expression. In general, DNA methylation is stably maintained in somatic tissues. However, DNA methylation patterns and levels show dynamic changes during development. Specifically, the genome undergoes two waves of global demethylation and remethylation for the purpose of producing the next generation. The first wave occurs in the germline, initiated with the erasure of global methylation in primordial germ cells (PGCs) and completed with the establishment of sex-specific methylation patterns during later stages of germ cell development. The second wave occurs after fertilization, including the erasure of most methylation marks inherited from the gametes and the subsequent establishment of the embryonic methylation pattern. The two waves of DNA methylation reprogramming involve both distinct and shared mechanisms. In this review article, we provide an overview of the key reprogramming events, focusing on the important players in these processes, including DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) family of 5mC dioxygenases.

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