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| Status |
Public on Mar 18, 2020 |
| Title |
Genome-wide targeted methyl-seq: Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs I |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by high throughput sequencing
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| Summary |
Background: Mapping of allele-specific methylation (ASM) can be a post-GWAS strategy for localizing functional regulatory sequence polymorphisms (rSNPs). However, the unique advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified.
Results: We performed sequence capture-based (25 samples, including 14 newly sequenced samples) and whole genome bisulfite sequencing (81 samples) on diverse normal human cells and tissues from multiple individuals, plus a group of cancers (multiple myeloma, lymphoma, and glioblastoma multiforme). After excluding imprinting, the data pinpointed 15,114 high-confidence ASM differentially methylated regions (DMRs), of which 1,842 contained SNPs in strong linkage disequilibrium or coinciding with GWAS peaks. ASM frequencies were increased 5 to 9-fold in cancers vs. matched normal tissues, due to widespread allele-specific hypomethylation and focal allele-specific hypermethylation in poised chromatin. Cancers showed increased allele switching at ASM loci, but destructive SNPs in specific classes of CTCF and transcription factor (TF) binding motifs were similarly correlated with ASM in cancer and non-cancer. Rare somatic mutations in these same motif classes tracked with de novo ASM in the cancers. Allele-specific TF binding from ChIP-seq was enriched among ASM loci, but most ASM DMRs lacked such annotations, and some were found in otherwise uninformative “chromatin deserts”.
Conclusions: ASM is increased in cancers but occurs by a shared mechanism involving rSNPs in CTCF and TF binding sites in normal and neoplastic cells. Dense ASM mapping in normal plus cancer samples reveals candidate rSNPs that are difficult to find by other approaches. Together with GWAS data, these rSNPs can nominate specific transcriptional pathways in susceptibility to autoimmune, neuropsychiatric, and neoplastic diseases.
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| Overall design |
Agilent SureSelect methyl-seq DNA hybrid capture kit was used according to the manufacturer’s instructions. DNA was sheared to an average size of 200 bp and bisulfite converted with the EZ DNA methylation kit (Zymo). Paired end reads (100 bp, 150 or 250 bp) were generated at the Genomics Shared Resource of the Herbert Irving Comprehensive Cancer Center of Columbia University, with an Illumina HiSeq2500 sequencer. After trimming for low-quality bases (Phred score<30) and reads with a length <40 bp with TrimGalore, the reads were aligned to the human genome (GRCh37) using Bismark with paired end mode and default setting. Unpaired reads after trimming were aligned separately using single end-mode and the same settings. Duplicate reads were removed using Picard tools.
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| Contributor(s) |
Do C, Dumont E, Salas M, Castano A, Mujahed H, Maldonado L, Singh A, Bhagat G, Lehman S, Christiano AM, Madhavan S, Nagy0 PL, Green PH, Ilsey N, Feinman R, Trimble C, Marder K, Honig L, Monk C, Goy A, Chow K, Goldlust S, Kaptain G, Siegel D, Tycko B |
| Citation(s) |
32594908 |
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| Submission date |
Sep 11, 2019 |
| Last update date |
Feb 27, 2023 |
| Contact name |
Benjamin Tycko |
| E-mail(s) |
bejamintycko@hackensackmeridian.org
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| Phone |
5519963595
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| Organization name |
HUMC
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| Department |
Epigenetics
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| Street address |
40 prospect avenue
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| City |
hackensack |
| State/province |
NJ |
| ZIP/Postal code |
07601 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (14)
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| This SubSeries is part of SuperSeries: |
| GSE137880 |
Whole genome bisulfite sequencing and Genome-wide targeted methyl-seq: Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs |
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| Relations |
| BioProject |
PRJNA565006 |
| SRA |
SRP221387 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE137287_RAW.tar |
630.0 Kb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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