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

Catherine Do, Catherine Do, Emmanuel L.P. Dumont, Emmanuel L.P. Dumont, Martha Salas, Martha Salas, Angelica Castano, Angelica Castano, Huthayfa Mujahed, Leonel Maldonado, Arunjot Singh, Sonia C. Dasilva-Arnold, Govind Bhagat, Govind Bhagat, Soren Lehman, Angela M. Christiano, Subha Madhavan, Peter L. Nagy, Peter H.R. Green, Rena FeinmanRena Feinman, Rena Feinman, Cornelia Trimble, Nicholas P. Illsley, Karen Marder, Karen Marder, Lawrence Honig, Lawrence Honig, Catherine Monk, Andre Goy, Andre Goy, Andre Goy, Kar Chow, Kar Chow, Kar Chow, Samuel Goldlust, Samuel Goldlust, George Kaptain, George Kaptain, David Siegel, David Siegel, David Siegel, Benjamin Tycko, Benjamin Tycko, Benjamin Tycko

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). The advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified. Results: We perform whole genome methyl-seq on diverse normal cells and tissues and three cancer types. After excluding imprinting, the data pinpoint 15,112 high-confidence ASM differentially methylated regions, of which 1838 contain SNPs in strong linkage disequilibrium or coinciding with GWAS peaks. ASM frequencies are increased in cancers versus matched normal tissues, due to widespread allele-specific hypomethylation and focal allele-specific hypermethylation in poised chromatin. Cancer cells show increased allele switching at ASM loci, but disruptive SNPs in specific classes of CTCF and transcription factor binding motifs are similarly correlated with ASM in cancer and non-cancer. Rare somatic mutations affecting these same motif classes track with de novo ASM. Allele-specific transcription factor binding from ChIP-seq is enriched among ASM loci, but most ASM differentially methylated regions lack such annotations, and some are found in otherwise uninformative "chromatin deserts."Conclusions: ASM is increased in cancers but occurs by a shared mechanism involving disruptive SNPs in CTCF and transcription factor binding sites in both 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, cardiometabolic, neuropsychiatric, and neoplastic diseases.

Original languageEnglish (US)
Article number153
JournalGenome biology
Volume21
Issue number1
DOIs
StatePublished - Jun 29 2020

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

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