Genome-wide tracking of unmethylated DNA Alu repeats in normal and cancer cells

Rodríguez, Jairo; Vives, Laura; Jordá, Mireia; Morales, Cristina; Muñoz, Mar; Vendrell, Elisenda; Peinado, Miguel A.

doi:10.1093/nar/gkm1105

Cited by 91 publications

(67 citation statements)

References 73 publications

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“…In humans, most of the methylated cytosines are found in CpG-rich sequences within tandem and interspersed repeats that constitute up to 45% of the human genome, and Alu repeats are the most common family of such repeats. We used genome-wide amplification of unmethylated DNA Alu repeats (AUMA) (Rodriguez et al 2008) to Figure 2. A comparison of the DNA methylation levels of eight genes in paired samples discordant for SLE.…”

Section: Resultsmentioning

confidence: 99%

Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus

Javierre¹,

Fernández²,

Richter³

et al. 2009

Genome Res.

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Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.[Supplemental material is available online at http://www.genome.org. The sequence data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE19033.]Human monozygotic (MZ) twins exhibit variable degrees of concordance for complex diseases, such as cancer, cardiovascular diseases, or autoimmune disorders. Whereas concordance rates close to 100% in identical twins apply to coinheritance of mutant genes that are dominant and highly penetrant, most diseases or traits show a concordance in identical twins in the broad range of 5%-75% (Nance 1978). Most of the twin-based studies have focused on the concordance between siblings that has led to the identification of traitspecific genes (Hrubec and Robinette 1984), while less attention has been paid to the degree of discordance, which suggests the participation of factors other than pure genetic changes. Recently, interest has shifted toward exploring the molecular mechanisms involved in determining phenotypic differences. The increasing recognition of the influence of epigenetics in phenotypic outcomes continues to open up new lines of research involving twin studies. DNA methylation and histone modifications, the major sources of epigenetic information, regulate gene expression levels and provide an alternative mechanism for modulating gene function to those arising from genetic changes (Esteller 2008). Interestingly, epigenetic changes are

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Section: Resultsmentioning

confidence: 99%

Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus

Javierre¹,

Fernández²,

Richter³

et al. 2009

Genome Res.

Self Cite

585

433

View full text Add to dashboard Cite

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“…Total RNAs were isolated from control cells and heat shocked HeLa cells using Tri families which show striking differences in their methylation level. 54,55 Alternatively, this non-demethylation of Alu elements in DKO cells might also suggest that additional methylating activities are involved at those loci. In this regard, the study by Kato et al 56 suggests that mouse sineB1 repeats are preferentially methylated by DNMT3a and DNMT3L enzymes.…”

Section: Methodsmentioning

confidence: 99%

Global analysis of DNA methylation and transcription of human repetitive sequences.

Horard¹,

Eymery²,

Fourel³

et al. 2009

Epigenetics

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Epigenetics 339Half of the human genome consists of repetitive DNA sequences. Recent studies in various organisms highlight the role of chromatin regulation of repetitive DNA in gene regulation as well as in maintainance of chromosomes and genome integrity. Hence, repetitive DNA sequences might be potential "sensors" for chromatin changes associated with pathogenesis. Therefore, we developed a new genomic tool called RepArray. RepArray is a repeat-specific microarray composed of a representative set of human repeated sequences including transposon-derived repeats, simple sequences repeats, tandemly repeated sequences such as centromeres and telomeres. We showed that combined to anti-methylcytosine immunoprecipitation assay, the RepArray can be used to generate repeat-specific methylation maps. Using cell lines impaired chemically or genetically for DNA methyltransferases activities, we were able to distinguish different epigenomes demonstrating that repeats can be used as markers of genome-wide methylation changes. Besides, using a well-documented system model, the thermal stress, we demonstrated that RepArray is also a fast and reliable tool to obtain an overview of overall transcriptional activity on whole repetitive compartment in a given cell type. Thus, the RepArray represents the first valuable tool for systematic and genome-wide analyses of the methylation and transcriptional status of the repetitive counterpart of the human genome.

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“…Positive and negative controls for each histone modification were used to set the lower limits. 3,6,49 Amplification primers for gene promoters are listed in Supplemental Table 3. PCRs were performed in triplicate.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Dynamics of bivalent chromatin domains upon drug induced reactivation and resilencing in cancer cells

Mayor

Muñoz²,

Coolen³

et al. 2011

Epigenetics

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Genome-wide tracking of unmethylated DNA Alu repeats in normal and cancer cells

Cited by 91 publications

References 73 publications

Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus

Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus

Global analysis of DNA methylation and transcription of human repetitive sequences.

Dynamics of bivalent chromatin domains upon drug induced reactivation and resilencing in cancer cells

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