Epigenomic analysis of Alu repeats in human ependymomas.
Global loss of DNA methylation has been known for decades as an epigenomic aberration associated with carcinogenesis and cancer progression. Loss of DNA methylation affects predominantly repetitive elements, which encompass >50% of the CpG dinucleotides present in the human genome. Because of the lack of an effective approach, no studies have been conducted to reveal such genome-wide methylation changes at a single-base resolution. To precisely determine the CpG sites with methylation loss during progression of pediatric intracranial ependymomas, we exploited a high-throughput bisulfite sequencing approach that simultaneously generates methylation profiles for thousands of Alu elements and their flanking sequences. Comparison of the methylation profiles of normal and tumor tissues revealed that the methylation status of the majority of CpG sites adjacent to or within Alu repeats remain unaltered, while a small set of CpG sites gain or lose methylation in ependymomas. Compared to the CpG sites with stable methylation level between normal control and ependymomas, the differentially methylated CpG sites are enriched in the sequences with low CpG density in the flanking regions of Alu repeats, rather than within the Alu sequences themselves. In addition, the CpG sites that are hypermethylated in ependymomas are proximal to CpG islands, whereas those that are hypomethylated are overrepresented in intergenic regions. Lastly, aberrant methylation of several genomic loci was confirmed to be associated with the aggressive primary tumors and the relapsed ependymomas.
Xie
Hehuang
H
Falk Brain Tumor Center, Cancer Biology and Epigenomics Program, Feinberg School of Medicine, Northwestern University, Chicago, IL 60614-3394, USA. hxie@childrensmemorial.org
Wang
Min
M
Bonaldo
Maria de F
Mde F
Rajaram
Veena
V
Stellpflug
Wendy
W
Smith
Christina
C
Arndt
Kelly
K
Goldman
Stewart
S
Tomita
Tadanori
T
Soares
Marcelo B
MB
D020087:Alu Elements / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D004806:Ependymoma / Q000235:genetics*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D008957:Models, Genetic; D009711:Nucleotides; D011379:Prognosis; D013447:Sulfites
D009711:Nucleotides; D013447:Sulfites; C042345:hydrogen sulfite