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
Posted on 2020-06-29 - 03:12
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.
CITE THIS COLLECTION
DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
Do, Catherine; Dumont, Emmanuel L. P.; Salas, Martha; Castano, Angelica; Mujahed, Huthayfa; Maldonado, Leonel; et al. (2020). 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. figshare. Collection. https://doi.org/10.6084/m9.figshare.c.5043173.v1
or
Select your citation style and then place your mouse over the citation text to select it.
SHARE
Usage metrics
AUTHORS (26)
CD
Catherine Do
ED
Emmanuel L. P. Dumont
MS
Martha Salas
AC
Angelica Castano
HM
Huthayfa Mujahed
LM
Leonel Maldonado
AS
Arunjot Singh
SD
Sonia C. DaSilva-Arnold
GB
Govind Bhagat
SL
Soren Lehman
AC
Angela M. Christiano
SM
Subha Madhavan
PN
Peter L. Nagy
PG
Peter H. R. Green
RF
Rena Feinman
CT
Cornelia Trimble
NI
Nicholas P. Illsley
KM
Karen Marder
LH
Lawrence Honig
CM
Catherine Monk
KEYWORDS
transcription factor binding motifsallele-specific DNA methylationCTCFGWASneoplastic cellsAllele-specific transcription facto...ASM differentially methylated regio...SNPs Abstract Background MappingDense ASM mappingtranscription factor binding sitescancer cells showmotif classes trackASM lociAllele-specific DNA methylationneoplastic cells increases