Dataset Information

A subset of methylated CpG sites differentiate psoriatic from normal skin.

ABSTRACT: Psoriasis is a chronic inflammatory immune-mediated disorder affecting the skin and other organs including joints. Over 1,300 transcripts are altered in psoriatic involved skin compared with normal skin. However, to our knowledge, global epigenetic profiling of psoriatic skin is previously unreported. Here, we describe a genome-wide study of altered CpG methylation in psoriatic skin. We determined the methylation levels at 27,578 CpG sites in skin samples from individuals with psoriasis (12 involved, 8 uninvolved) and 10 unaffected individuals. CpG methylation of involved skin differed from normal skin at 1,108 sites. Twelve mapped to the epidermal differentiation complex, upstream or within genes that are highly upregulated in psoriasis. Hierarchical clustering of 50 of the top differentially methylated (DM) sites separated psoriatic from normal skin samples with uninvolved skin exhibiting intermediate methylation. CpG sites where methylation was correlated with gene expression are reported. Sites with inverse correlations between methylation and nearby gene expression include those of KYNU, OAS2, S100A12, and SERPINB3, whose strong transcriptional upregulation is an important discriminator of psoriasis. Pyrosequencing of bisulfite-treated DNA from skin biopsies at three DM loci confirmed earlier findings and revealed reversion of methylation levels toward the non-psoriatic state after 1 month of anti-TNF-? therapy.

SUBMITTER: Roberson ED

PROVIDER: S-EPMC3568942 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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A subset of methylated CpG sites differentiate psoriatic from normal skin.

Roberson Elisha D O ED Liu Ying Y Ryan Caitriona C Joyce Cailin E CE Duan Shenghui S Cao Li L Martin Ann A Liao Wilson W Menter Alan A Bowcock Anne M AM

The Journal of investigative dermatology 20111110 3 Pt 1

Psoriasis is a chronic inflammatory immune-mediated disorder affecting the skin and other organs including joints. Over 1,300 transcripts are altered in psoriatic involved skin compared with normal skin. However, to our knowledge, global epigenetic profiling of psoriatic skin is previously unreported. Here, we describe a genome-wide study of altered CpG methylation in psoriatic skin. We determined the methylation levels at 27,578 CpG sites in skin samples from individuals with psoriasis (12 invo ...[more]

PMID: 22071477

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Project description:BACKGROUND:Psychiatric symptomatology during late childhood and early adolescence tends to persist later in life. In the present longitudinal study, we aimed to identify changes in genome-wide DNA methylation patterns that were associated with the emergence of psychopathology in youths from the Brazilian High-Risk Cohort (HRC) for psychiatric disorders. Moreover, for the differentially methylated genes, we verified whether differences in DNA methylation corresponded to differences in mRNA transcript levels by analyzing the gene expression levels in the blood and by correlating the variation of DNA methylation values with the variation of mRNA levels of the same individuals. Finally, we examined whether the variations in DNA methylation and mRNA levels were correlated with psychopathology measurements over time. METHODS:We selected 24 youths from the HRC who presented with an increase in dimensional psychopathology at a 3-year follow-up as measured by the Child Behavior Checklist (CBCL). The DNA methylation and gene expression data were compared in peripheral blood samples (n?=?48) obtained from the 24 youths before and after developing psychopathology. We implemented a methodological framework to reduce the effect of chronological age on DNA methylation using an independent population of 140 youths and the effect of puberty using data from the literature. RESULTS:We identified 663 differentially methylated positions (DMPs) and 90 differentially methylated regions (DMRs) associated with the emergence of psychopathology. We observed that 15 DMPs were mapped to genes that were differentially expressed in the blood; among these, we found a correlation between the DNA methylation and mRNA levels of RB1CC1 and a correlation between the CBCL and mRNA levels of KMT2E. Of the DMRs, three genes were differentially expressed: ASCL2, which is involved in neurogenesis; HLA-E, which is mapped to the MHC loci; and RPS6KB1, the gene expression of which was correlated with an increase in the CBCL between the time points. CONCLUSIONS:We observed that changes in DNA methylation and, consequently, in gene expression in the peripheral blood occurred concurrently with the emergence of dimensional psychopathology in youths. Therefore, epigenomic modulations might be involved in the regulation of an individual's development of psychopathology.

Project description:Determining the role of DNA methylation in various biological processes is dependent on the accurate representation of often highly complex patterns. Accurate representation is dependent on unbiased PCR amplification post bisulfite modification, regardless of methylation status of any given epiallele. This is highly dependent on primer design. Particular difficulties are raised by the analysis of CpG-rich regions, which are the usual regions of interest. Here, it is often difficult or impossible to avoid placing primers in CpG-free regions, particularly if one wants to target a specific part of a CpG-rich region. This can cause biased amplification of methylated sequences if the C is placed at those positions or to unmethylated sequences if a T is placed at those positions.We examined the effect of various base substitutions at the cytosine position of primer CpGs on the representational amplification of templates and also examined the role of the annealing temperature during PCR. These were evaluated using methylation-sensitive high-resolution melting and Pyrosequencing.For a mixture of fully methylated and unmethylated templates, amplification using the C-, C/T (Y-) and inosine-containing primers was biased towards amplification of methylated DNA. The bias towards methylated sequences increased with annealing temperature. Amplification using primers with an A/C/G/T (N) degeneracy at the cytosine positions was not biased at the lowest temperature used but became increasingly biased towards methylated DNA with increased annealing temperature. Using primers matching neither C nor T was in the main unbiased but at the cost of poor PCR amplification efficiency. Primers with abasic sites were also unbiased but could only amplify DNA for one out of the two assays tested. However, with heterogeneous methylation, it appeared that both the primer type and stringency used have a minimal influence on PCR bias.This is the first comprehensive analysis of base substitutions at CpG sites in primers and their effect on PCR bias for the analysis of DNA methylation. Our findings are relevant to the appropriate design of a wide range of assays, including amplicon-based next-generation sequencing approaches that need to measure DNA methylation.

Dataset Information

A subset of methylated CpG sites differentiate psoriatic from normal skin.

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A subset of methylated CpG sites differentiate psoriatic from normal skin.

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