TY - JOUR
T1 - 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
AU - Do, Catherine
AU - Do, Catherine
AU - Dumont, Emmanuel L.P.
AU - Dumont, Emmanuel L.P.
AU - Salas, Martha
AU - Salas, Martha
AU - Castano, Angelica
AU - Castano, Angelica
AU - Mujahed, Huthayfa
AU - Maldonado, Leonel
AU - Singh, Arunjot
AU - Dasilva-Arnold, Sonia C.
AU - Bhagat, Govind
AU - Bhagat, Govind
AU - Lehman, Soren
AU - Christiano, Angela M.
AU - Madhavan, Subha
AU - Nagy, Peter L.
AU - Green, Peter H.R.
AU - Feinman, Rena
AU - Feinman, Rena
AU - Feinman, Rena
AU - Trimble, Cornelia
AU - Illsley, Nicholas P.
AU - Marder, Karen
AU - Marder, Karen
AU - Honig, Lawrence
AU - Honig, Lawrence
AU - Monk, Catherine
AU - Goy, Andre
AU - Goy, Andre
AU - Goy, Andre
AU - Chow, Kar
AU - Chow, Kar
AU - Chow, Kar
AU - Goldlust, Samuel
AU - Goldlust, Samuel
AU - Kaptain, George
AU - Kaptain, George
AU - Siegel, David
AU - Siegel, David
AU - Siegel, David
AU - Tycko, Benjamin
AU - Tycko, Benjamin
AU - Tycko, Benjamin
N1 - Publisher Copyright:
© 2020 The Author(s).
PY - 2020/6/29
Y1 - 2020/6/29
N2 - 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.
AB - 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.
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U2 - 10.1186/s13059-020-02059-3
DO - 10.1186/s13059-020-02059-3
M3 - Article
C2 - 32594908
AN - SCOPUS:85087144320
SN - 1474-7596
VL - 21
JO - Genome biology
JF - Genome biology
IS - 1
M1 - 153
ER -