Unknown,Transcriptomics,Genomics,Proteomics

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Comparison of the methylation profiles of children with developmental language disorder and healthy control subjects

ABSTRACT: Developmental language disorder (DLD), previously known as specific language impairment, is a neurodevelopmental disorder. It affects approximately 7% of school-age children. The affected children fail to develop normal speech and language skills. This is a major public health concern as it adversely impacts the communication, academic, and social skills of the affected individual. The human brain development is a complex process that involves the accurate orchestration of the expression of multiple genes. Precise temporal and spatial regulation of gene expression is essential for proper brain development. Epigenetic factors such as DNA methylation can modulate gene expression without altering the DNA sequence. They are, therefore, considered as key regulators of the expression of genes involved in neurodevelopment. In this study, we examined any altered DNA methylation between children affected with DLD and healthy control subjects. We looked into genome-wide methylation differences between the DLD and control groups using Infinium HumanMethylation850 (EPICarray). Twelve children with DLD and 12 healthy controls were recruited for the study. Five milliliters of peripheral blood samples were collected from the study subjects in EDTA vials. Genomic DNA (gDNA) was extracted from the blood samples using the standard salting out protocol. Five micrograms of each DNA at 50 ng/µl concentration were used for genome-wide methylation analysis. The gDNA samples were bisulfite-treated with EpiTect Bisulfite Kit. Further to this, the DNA samples were subjected to whole genome amplification and enzymatic fragmentation. Human Infinium Methylation EPIC BeadChip (Illumina), which covers more than 850,000 genome-wide methylation sites, was used for genome-wide methylation analysis. The DNA methylation profiles of each sample were visualized at the single-CpG level and for the genomic regions of interest.

ORGANISM(S): Homo sapiens

SUBMITTER: Ayyappan Anitha

PROVIDER: E-MTAB-13583 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Colorectal cancer (CRC) is the third most deadly and fourth most diagnosed cancer worldwide. Despite the progress in early diagnosis and advanced therapeutic options, CRC shows a poor prognosis with a 5-year survival rate of ~45%. PRDM2/RIZ, a member of Positive Regulatory Domain (PRDM) gene family, expresses two main molecular variants, the PR-plus isoform (RIZ1) and the PR-minus (RIZ2). The imbalance in their expression levels in favour of RIZ2 is observed in many cancer types. The full length RIZ1 has been extensively investigated in several cancers where it acts as a tumour suppressor, whereas few studies have explored the RIZ2 oncogenic properties. PRDM2 is often target of frameshift mutations and aberrant DNA methylation in CRC. Accordingly, our analysis of Exome- and transcriptome public datasets available at The Cancer Genome Atlas (TCGA) portal revealed that PRDM2 gene is frequently mutated and transcriptionally deregulated in CRC. However, little is known about its role in CRC. In this study, we first evaluated the expression of the different PRDM2 transcripts by in silico analysis on TCGA CRC datasets. Our in-silico analysis on TCGA datasets revealed a highly significant downregulation of RIZ1 in CRC samples whereas a RIZ2 increase was observed in the same samples. Then, we assayed several CRC cell lines by qRT-PCR analysis for the main PRDM2 transcripts and selected DLD-1 cell line, which showed the lowest RIZ2 levels to mimic TCGA datasets analysis results and consequently to assess the PRDM2/RIZ2 role in CRC cells. RNAseq analysis revealed that RIZ2 overexpression induced an EGF overexpression suggesting that RIZ2 could be involved in the EGF autocrine regulation of DLD-1 cell behaviour. Noteworthy, the forced RIZ2 expression increased cell viability, growth, colony formation, migration and organoid formation thus confirming our previous findings on HEK-293 cells. These effects could be mediated by the release of high EGF levels by RIZ2 overexpressing DLD-1 cells. Our findings add novel insights on the putative RIZ2 tumor-promoting functions in CRC, although additional attempts are warranted to depict the underlying molecular mechanism of action

Project description:Background: Nasal epithelia are emerging as a proxy measure of gene expression of the airway epithelium in asthma. We hypothesized that epigenetic marks regulate gene expression of the nasal epithelia and consequently may provide a novel target for allergic asthma. Methods: We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma [N=36] versus healthy controls [N=36]. Results were validated in an independent population of asthmatics [N=30]. Results: We identified 186 genes with significant methylation changes, either as regions (differentially methylated regions [DMRs]) or single CpGs (differentially methylated probes [DMPs]) after adjustment for age, gender, race/ethnicity, batch effects, inflation, and multiple comparisons (false discovery rate-adjusted q<0.05). Genes differentially methylated include those with established roles in asthma and atopy, components of the extracellular matrix, genes related to immunity, cell adhesion, epigenetic regulation, and airway obstruction. The methylation changes are large (median 9.5%, range: 2.6-29.5% methylation change) and similar in magnitude to those observed in malignancies. Hypo- and hyper-methylated genes were associated with increased and decreased gene expression respectively (P<2.8x10-6 for DMRs and P<7.8x10-10 for DMPs). Quantitative analysis of methylation-expression relationships in 53 differentially expressed genes demonstrated that 32 (60%) have significant (q<0.05) methylation-expression relationships within 5kb of the gene. 10 loci selected based on the relevance to asthma, magnitude of methylation change, and asthma specific methylation-expression relationships were validated in an independent cohort of children with asthma. Conclusions: Our findings that epigenetic marks in respiratory epithelia are associated with allergic asthma in inner-city children provide new targets for biomarker development, and novel approaches to understanding disease pathogenesis. case control design with nasal epithelial cells from 36 atopic asthmatic and 36 nonatopic nonasthmatic children from the inner city

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Comparison of the methylation profiles of children with developmental language disorder and healthy control subjects

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