Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Global DNA Hypermethylation in Down Syndrome Placenta [Bisulfite-Seq]

ABSTRACT: We have performed genome-wide DNA methylation analysis at single base resolution and gene expression analysis, resulted in hypermethylation in all autosomes in DS samples, mediated by down-regulation of all three TET family genes, and down-regulation of REST/NRSF. Genes located on chr21 were up-regulated by a median of 45% in DS compared to normal villi, while genes with promoter hypermethylation were down regulated. DNA methylation comparison in human placenta between 6 normal and 11 Trisomy 21 samples

ORGANISM(S): Homo sapiens

SUBMITTER: Chunming Ding

PROVIDER: E-GEOD-42074 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Global DNA hypermethylation in down syndrome placenta.

Jin Shengnan S Lee Yew Kok YK Lim Yen Ching YC Zheng Zejun Z Lin Xueqin Michelle XM Ng Desmond P Y DP Holbrook Joanna D JD Law Hai Yang HY Kwek Kenneth Y C KY Yeo George S H GS Ding Chunming C

PLoS genetics 20130606 6

Down syndrome (DS), commonly caused by an extra copy of chromosome 21 (chr21), occurs in approximately one out of 700 live births. Precisely how an extra chr21 causes over 80 clinically defined phenotypes is not yet clear. Reduced representation bisulfite sequencing (RRBS) analysis at single base resolution revealed DNA hypermethylation in all autosomes in DS samples. We hypothesize that such global hypermethylation may be mediated by down-regulation of TET family genes involved in DNA demethyla ...[more]

PMID: 23754950

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Project description:Background: Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood. Results: Here, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T-lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in brain cells. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl-cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites, implicating a mechanism involving altered transcription factor binding. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects. Conclusions: These data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning. Bisulfite converted DNA from 119 samples from Down syndrome patients and controls were hybridised to the Illumina Infinium 450k Human Methylation Beadchip. In addition, we re-analyzed 6 Down syndrome and 6 control cerebellum DNA samples on the 450K BeadChips using an adaptation of the Illumina probe preparation protocol (TrueMethyl kit; Cambridge Epigenetics, CEGX), in which parallel analyses of bisulfite and oxidative bisulfite DNA for each sample allows assessment of the relative contributions of 5mC and 5hmC to net methylation.

Project description:DCIS is a non-invasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer while others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor intrinsic subtypes, proliferative, immune scores and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immune suppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly ncRNA and methylation profiles reproduce changes observed post-invasion. Among the most significant findings we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and specific SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a pre-invasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer. DNA from 24 out of 30 (80%) HG-DCIS samples and 5 normal breast organoids (total 29 samples) were subjected to reduced representation bisulfite sequencing analysis (RRBS) by using Illumina HiSeq2000 platform. Please note that description of samples employed for the NGS analyses including age, race, ER/PR immunohistochemistry results, ITIL/STIL scores and PAM50 classification is provided the 'Supplementary Data1_Samples data.xlsx' (available on Superseries record)

Dataset Information

Global DNA Hypermethylation in Down Syndrome Placenta [Bisulfite-Seq]

Publications

Global DNA hypermethylation in down syndrome placenta.

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