DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes

Epigenomics ◽  
2021 ◽  
Author(s):  
Beatriz Garcia-Ruiz ◽  
Manuel Castro de Moura ◽  
Gerard Muntané ◽  
Lourdes Martorell ◽  
Elena Bosch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Bipolar Disorder ◽  
Mrna Expression ◽  
Gene Expression Analysis ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Genome Wide ◽  
Isoform Expression

Aim: To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes. Materials & methods: Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. Results: DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes. Conclusion: DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

scholarly journals Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells

2018 ◽  
Author(s):  
Shaylynn Miller ◽  
Patrick Coit ◽  
Elizabeth Gensterblum-Miller ◽  
Paul Renauer ◽  
Nathan C Kilian ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Genome Wide

AbstractObjectiveWe examined genome-wide DNA methylation changes in CD8+ T cells from lupus patients and controls, and investigated the functional relevance of some of these changes in lupus.MethodsGenome-wide DNA methylation of lupus and age, sex, and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR.ResultsLupus CD8+ T cells had 188 hypomethylated CpG sites compared to healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFNα upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFNα. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFNα in lupus CD8+ T cells, but not healthy controls. Co-incubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69, in lupus patients but not in healthy controls. This can be blocked by neutralizing antibodies targeting HLA-DR.ConclusionsLupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFNα in lupus patients. A possible pathogenic role for CD8+ T cells in lupus that is dependent upon a high type-I interferon environment and epigenetic priming warrants further characterization.

scholarly journals DNA Methylation and Transcriptomic Features are Preserved Throughout Disease Recurrence and Chemoresistance in High Grade Serous Ovarian Cancers

2022 ◽  
Author(s):  
Nicole Gull ◽  
Michell Jones ◽  
Pei-Chen Peng ◽  
Simon Coetzee ◽  
Tiago Silva ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Bisulfite Sequencing ◽  
Disease Recurrence ◽  
High Grade ◽  
Chemotherapy Treatment ◽  
Recurrent Tumors ◽  
Genome Wide ◽  
Genome Bisulfite Sequencing

Abstract Background Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). We performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations. Results Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P=0.006) in these BRCA1/2 carriers. Conclusions These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC.

scholarly journals VRK2 gene expression in schizophrenia, bipolar disorder and healthy controls

2016 ◽  
Vol 209 (2) ◽  
pp. 114-120 ◽  
Author(s):  
Martin Tesli ◽  
Katrine Verena Wirgenes ◽  
Timothy Hughes ◽  
Francesco Bettella ◽  
Lavinia Athanasiu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bipolar Disorder ◽  
Association Studies ◽  
Mrna Level ◽  
Genome Wide Association Studies ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Schizophrenia Spectrum Disorders ◽  
Underlying Mechanisms

BackgroundCommon variants in the Vaccinia-related kinase 2 (VRK2) gene have been associated with schizophrenia, but the relevance of its encoded protein VRK2 in the disorder remains unclear.AimsTo identify potential differences in VRK2 gene expression levels between schizophrenia, bipolar disorder, psychosis not otherwise specified (PNOS) and healthy controls.MethodVRK2 mRNA level was measured in whole blood in 652 individuals (schizophrenia, n = 201; bipolar disorder, n = 167; PNOS, n = 61; healthy controls, n = 223), and compared across diagnostic categories and subcategories. Additionally, we analysed for association between 1566 VRK2 single nucleotide polymorphisms and mRNA levels.ResultsWe found lower VRK2 mRNA levels in schizophrenia compared with healthy controls (P<10–12), bipolar disorder (P<10–12) and PNOS (P = 0.0011), and lower levels in PNOS than in healthy controls (P = 0.0042) and bipolar disorder (P = 0.00026). Expression quantitative trait loci in close proximity to the transcription start site of the short isoforms of the VRK2 gene were identified.ConclusionsAltered VRK2 gene expression seems specific for schizophrenia and PNOS, which is in accordance with findings from genome-wide association studies. These results suggest that reduced VRK2 mRNA levels are involved in the underlying mechanisms in schizophrenia spectrum disorders.

scholarly journals Exogenous RNAi mechanisms contribute to transcriptome adaptation by phased siRNA clusters in Paramecium

2019 ◽  
Vol 47 (15) ◽  
pp. 8036-8049 ◽  
Author(s):  
Sivarajan Karunanithi ◽  
Vidya Oruganti ◽  
Simone Marker ◽  
Angela M Rodriguez-Viana ◽  
Franziska Drews ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Levels ◽  
Reading Frame ◽  
Transcriptome Regulation ◽  
Genome Wide ◽  
Exogenous Rna ◽  
Entire Open Reading Frame ◽  
Polymerase Mutants ◽  
Gene Expression Levels

Abstract Extensive research has characterized distinct exogenous RNAi pathways interfering in gene expression during vegetative growth of the unicellular model ciliate Paramecium. However, role of RNAi in endogenous transcriptome regulation, and environmental adaptation is unknown. Here, we describe the first genome-wide profiling of endogenous sRNAs in context of different transcriptomic states (serotypes). We developed a pipeline to identify, and characterize 2602 siRNA producing clusters (SRCs). Our data show no evidence that SRCs produce miRNAs, and in contrast to other species, no preference for strand specificity of siRNAs. Interestingly, most SRCs overlap coding genes and a separate group show siRNA phasing along the entire open reading frame, suggesting that the mRNA transcript serves as a source for siRNAs. Integrative analysis of siRNA abundance and gene expression levels revealed surprisingly that mRNA and siRNA show negative as well as positive associations. Two RNA-dependent RNA Polymerase mutants, RDR1 and RDR2, show a drastic loss of siRNAs especially in phased SRCs accompanied with increased mRNA levels. Importantly, most SRCs depend on both RDRs, reminiscent to primary siRNAs in the RNAi against exogenous RNA, indicating mechanistic overlaps between exogenous and endogenous RNAi contributing to flexible transcriptome adaptation.

scholarly journals Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes

2016 ◽  
Vol 75 (11) ◽  
pp. 2029-2036 ◽  
Author(s):  
Juliana Imgenberg-Kreuz ◽  
Johanna K Sandling ◽  
Jonas Carlsson Almlöf ◽  
Jessica Nordlund ◽  
Linnea Signér ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Salivary Gland ◽  
B Cells ◽  
Whole Blood ◽  
Minor Salivary Gland ◽  
Genome Wide ◽  
Induced Genes ◽  
Regulatory Effects

ObjectivesIncreasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls.MethodsGenome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed.ResultsWe identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed.ConclusionsOur study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.

scholarly journals Incorporation of DNA methylation into eQTL mapping in African Americans

2020 ◽  
Author(s):  
Anmol Singh ◽  
Yizhen Zhong ◽  
Layan Nahlawi ◽  
C. Sehwan Park ◽  
Tanima De ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
African Americans ◽  
Genetic Basis ◽  
Critical Role ◽  
Eqtl Analysis ◽  
Biliary Cirrhosis ◽  
Eqtl Mapping ◽  
Genome Wide

Epigenetics is a reversible molecular mechanism that plays a critical role in many developmental, adaptive, and disease processes. DNA methylation has been shown to regulate gene expression and the advent of high throughput technologies has made genome-wide DNA methylation analysis possible. We investigated the effect of DNA methylation in eQTL mapping (methylation-adjusted eQTLs), by incorporating DNA methylation as a SNP-based covariate in eQTL mapping in African American derived hepatocytes. We found that the addition of DNA methylation uncovered new eQTLs and eGenes. Previously discovered eQTLs were significantly altered by the addition of DNA methylation data suggesting that methylation may modulate the association of SNPs to gene expression. We found that methylation-adjusted eQTLs which were less significant compared to PC-adjusted eQTLs were enriched in lipoprotein measurements (FDR = 0.0040), immune system disorders (FDR = 0.0042), and liver enzyme measurements (FDR = 0.047), suggesting a role of DNA methylation in regulating the genetic basis of these phenotypes. Our methylation-adjusted eQTL analysis also uncovered novel SNP-gene pairs. For example, our study found the SNP, rs11546996, was associated to PNKP. In a previous GWAS, this SNP was associated with primary biliary cirrhosis although the causal gene was thought to be SPIB. Our methylation-adjusted method potentially adds new understanding to the genetic basis of complex diseases that disproportionally affect African Americans.

scholarly journals DNA Methylation Explains a Subset of Placental Gene Expression Differences Based on Ancestry and Altitude

2018 ◽  
Author(s):  
William E. Gundling ◽  
Priyadarshini Pantham ◽  
Nicholas P Illsley ◽  
Lourdes Echalar ◽  
Stacy Zamudio ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Birth Weight ◽  
Native Americans ◽  
High Altitude ◽  
Mrna Expression ◽  
European Ancestry ◽  
Gene Body Methylation ◽  
Genome Wide ◽  
Or Gene

Abstract:Objectives: The most pronounced effect of high altitude (>2700m) on reproductive outcomes is reduced birth weight. Indigenous Bolivians (Andean Native Americans) residing for generations at high altitudes have higher birth weights relative to more recent migrants of primarily European ancestry. Previous research demonstrated that the placenta is a key contributor to the preservation of Andean birth weight at high altitude. Our current research investigated how gene expression and epigenetics contributes to the conservation of birth weight at high altitude by examining mRNA expression and DNA methylation differences between placentas of Andeans and those of European ancestry residing at high and low altitude.Methods: Genome-wide mRNA expression and DNA methylation of villous placenta tissue was quantified utilizing microarray technology. Subjects were of Andean and European ancestry and resident at high (3600m) or low (400m) altitudes. Differentially expressed genes (DEGs) associated with altitude or ancestry were identified (FDR<0.1, |fold change|>1.25). To predict which DEGs could be regulated by methylation we tested for correlation between gene expression and methylation values.Results: 69 DEGs associated with altitude (n=36) or ancestry (n=34) were identified. Altitude-associated DEGs included members of the AP-1 transcription factor family. Ancestry-associated DEGs were implicated in inflammatory pathways and associated with pro-angiogenic macrophages. More ancestry-associated DEGs correlated significantly (n=17) (FDR<0.1) with promoter or gene body methylation (p=0.0242) when compared to altitude associated DEGs (n=8).Conclusions:Compared to altitude-associated DEGs, methylation regulates more ancestry-associated DEGs, potentially allowing for rapid modification in the expression of inflammatory genes to attract pro-angiogenic macrophages as a means of promoting placental capillary growth in Andeans, regardless of altitude.

scholarly journals Recent progress towards understanding the role of DNA methylation in human placental development

Reproduction ◽  
2016 ◽  
Vol 152 (1) ◽  
pp. R23-R30 ◽  
Author(s):  
Tina Bianco-Miotto ◽  
Benjamin T Mayne ◽  
Sam Buckberry ◽  
James Breen ◽  
Carlos M Rodriguez Lopez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Pregnancy Complications ◽  
Large Scale ◽  
Developmental Stages ◽  
Epigenetic Modifications ◽  
Placental Development ◽  
Functional Changes ◽  
Genome Wide

Epigenetic modifications, and particularly DNA methylation, have been studied in many tissues, both healthy and diseased, and across numerous developmental stages. The placenta is the only organ that has a transient life of 9 months and undergoes rapid growth and dynamic structural and functional changes across gestation. Additionally, the placenta is unique because although developing within the mother, its genome is identical to that of the foetus. Given these distinctive characteristics, it is not surprising that the epigenetic landscape affecting placental gene expression may be different to that in other healthy tissues. However, the role of epigenetic modifications, and particularly DNA methylation, in placental development remains largely unknown. Of particular interest is the fact that the placenta is the most hypomethylated human tissue and is characterized by the presence of large partially methylated domains (PMDs) containing silenced genes. Moreover, how and why the placenta is hypomethylated and what role DNA methylation plays in regulating placental gene expression across gestation are poorly understood. We review genome-wide DNA methylation studies in the human placenta and highlight that the different cell types that make up the placenta have very different DNA methylation profiles. Summarizing studies on DNA methylation in the placenta and its relationship with pregnancy complications are difficult due to the limited number of studies available for comparison. To understand the key steps in placental development and hence what may be perturbed in pregnancy complications requires large-scale genome-wide DNA methylation studies coupled with transcriptome analyses.

scholarly journals Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells

2019 ◽  
Vol 78 (4) ◽  
pp. 519-528 ◽  
Author(s):  
Shaylynn Miller ◽  
Pei-Suen Tsou ◽  
Patrick Coit ◽  
Elizabeth Gensterblum-Miller ◽  
Paul Renauer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Genome Wide

ObjectiveWe examined genome-wide DNA methylation changes in CD8+ T cells from patients with lupus and controls and investigated the functional relevance of some of these changes in lupus.MethodsGenome-wide DNA methylation of lupus and age, sex and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR. Inhibiting STAT1 and CIITA was performed using fludarabine and CIITA siRNA, respectively.ResultsLupus CD8+ T cells had 188 hypomethylated CpG sites compared with healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFNα upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFNα. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFNα in lupus CD8+ T cells, but not healthy controls. CIITA knockdown and STAT1 inhibition experiments revealed that HLA-DRB1 expression in lupus CD8+ T cells is dependent on CIITA and STAT1 signalling. Coincubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69 and cytokine production, in patients with lupus but not in healthy controls. This can be blocked by neutralising antibodies targeting HLA-DR.ConclusionsLupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFNα in patients with lupus. A possible pathogenic role for CD8+ T cells in lupus that is dependent on a high type-I interferon environment and epigenetic priming warrants further characterisation.

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