Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation.
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ABSTRACT:
SUBMITTER: Brinkman AB
PROVIDER: S-EPMC6465362 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
Publications
Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation.
Brinkman Arie B AB Nik-Zainal Serena S Simmer Femke F Rodríguez-González F Germán FG Smid Marcel M Alexandrov Ludmil B LB Butler Adam A Martin Sancha S Davies Helen H Glodzik Dominik D Zou Xueqing X Ramakrishna Manasa M Staaf Johan J Ringnér Markus M Sieuwerts Anieta A Ferrari Anthony A Morganella Sandro S Fleischer Thomas T Kristensen Vessela V Gut Marta M van de Vijver Marc J MJ Børresen-Dale Anne-Lise AL Richardson Andrea L AL Thomas Gilles G Gut Ivo G IG Martens John W M JWM Foekens John A JA Stratton Michael R MR Stunnenberg Hendrik G HG
Nature communications 20190415 1
Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. We comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of DNA ...[more]
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Project description:Astrocytomas are common and lethal human brain tumors. Here, we have analyzed the methylation status of over 28,000 CpG islands and 18,000 promoters in normal human brain and in astrocytomas of various grades using the methylated-CpG island recovery assay (MIRA). We identified six to seven thousand methylated CpG islands in normal human brain. ~5% of the promoter-associated CpG islands in normal brain are methylated. Promoter CpG island methylation is inversely and intragenic methylation is directly correlated with gene expression levels in brain tissue. In astrocytomas, several hundred CpG islands undergo specific hypermethylation relative to normal brain with 428 methylation peaks common to more than 25% of the tumors. Genes involved in brain development and neuronal differentiation, such as POU4F3, GDNF, OTX2, NEFM, CNTN4, OTP, SIM1, FYN, EN1, CHAT, GSX2, NKX6-1, RAX, PAX6, DLX2, were strongly enriched among genes frequently methylated in tumors. There was an overrepresentation of homeobox genes and 31% of the most commonly methylated genes represent targets of the Polycomb complex. We identified several chromosomal loci in which many (sometimes more than 20) consecutive CpG islands were hypermethylated in tumors. Seven of such loci were near homeobox genes, including the HOXC and HOXD clusters, and the BARHL2, DLX1, and PITX2 genes. Two other clusters of hypermethylated islands were at sequences of recent gene duplication events. Our analysis offers mechanistic insights into brain neoplasia suggesting that methylation of genes involved in neuronal differentiation, perhaps in cooperation with other oncogenic events, may shift the balance from regulated differentiation towards gliomagenesis. Comparison of methylation patterns of 30 astrocytomas and 6 controls
2010-05-16 | E-GEOD-19391 | biostudies-arrayexpress