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Passive and active DNA methylation and the interplay with genetic variation in gene regulation

DNA methylation is an essential1 epigenetic mark whose role in gene regulation and its dependency on genomic sequence and environment are not yet fully understood2,3. In this study we provide novel insights into the mechanistic relationships between genetic variation, DNA methylation and transcriptome sequencing data in three different cell-types of the GenCord human population cohort4. We find that the association between DNA methylation and gene expression variation among individuals are likely due to different mechanisms from those establishing methylation-expression patterns during differentiation. Furthermore, cell-type differential DNA methylation may delineate a platform in which more local inter-individual changes may respond to or act in gene regulation. We show that unlike genetic regulatory variation, DNA methylation alone does not significantly drive allele specific expression.. Finally, inferred mechanistic relationships using genetic variation as well as correlations with TF abundance reveal both a passive and active role of DNA methylation to regulatory interactions influencing gene expression.

Type: Population Genomics
Archiver: European Genome-phenome Archive (EGA)

3 Datasets 11 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001000425	GENCORD2 RNA-seq BAM files using BWA	Illumina Genome Analyzer II Illumina HiSeq 2000	568
EGAD00001000428	204 individuals were genotyped with the Illumina 2.5M Omni chip. Filtered genotypes were imputed into the 1000 genomes project European panel SNPs. Beagle R2 is indicated in VCF files for further filtering. See Materials and Methods in publication for details.		204
EGAD00010000460	GENCORD2 DNA methylation		294

Publications	Citations
Passive and active DNA methylation and the interplay with genetic variation in gene regulation. Gutierrez-Arcelus M, Lappalainen T, Montgomery SB, Buil A, Ongen H, Yurovsky A, Bryois J, Giger T, Romano L, Planchon A, Falconnet E, Bielser D, Gagnebin M, Padioleau I, Borel C, Letourneau A, Makrythanasis P, Guipponi M, Gehrig C, Antonarakis SE, Dermitzakis ET. Elife 2: 2013 e00523	348
The landscape of genomic imprinting across diverse adult human tissues. Baran Y, Subramaniam M, Biton A, Tukiainen T, Tsang EK, Rivas MA, Pirinen M, Gutierrez-Arcelus M, Smith KS, Kukurba KR, Zhang R, Eng C, Torgerson DG, Urbanek C, GTEx Consortium, Li JB, Rodriguez-Santana JR, Burchard EG, Seibold MA, MacArthur DG, Montgomery SB, Zaitlen NA, Lappalainen T. Genome Res 25: 2015 927-936	173
HIF3A association with adiposity: the story begins before birth. Pan H, Lin X, Wu Y, Chen L, Teh AL, Soh SE, Lee YS, Tint MT, MacIsaac JL, Morin AM, Tan KH, Yap F, Saw SM, Kobor MS, Meaney MJ, Godfrey KM, Chong YS, Gluckman PD, Karnani N, Holbrook JD, GUSTO Study Group. Epigenomics 7: 2015 937-950	52
Detection of Imprinted Genes by Single-Cell Allele-Specific Gene Expression. Santoni FA, Stamoulis G, Garieri M, Falconnet E, Ribaux P, Borel C, Antonarakis SE. Am J Hum Genet 100: 2017 444-453	55
Developmental pathways to adiposity begin before birth and are influenced by genotype, prenatal environment and epigenome. Lin X, Lim IY, Wu Y, Teh AL, Chen L, Aris IM, Soh SE, Tint MT, MacIsaac JL, Morin AM, Yap F, Tan KH, Saw SM, Kobor MS, Meaney MJ, Godfrey KM, Chong YS, Holbrook JD, Lee YS, Gluckman PD, Karnani N, GUSTO study group. BMC Med 15: 2017 50	87
Choice of surrogate tissue influences neonatal EWAS findings. Lin X, Teh AL, Chen L, Lim IY, Tan PF, MacIsaac JL, Morin AM, Yap F, Tan KH, Saw SM, Lee YS, Holbrook JD, Godfrey KM, Meaney MJ, Kobor MS, Chong YS, Gluckman PD, Karnani N. BMC Med 15: 2017 211	26
Identification of rare de novo epigenetic variations in congenital disorders. Barbosa M, Joshi RS, Garg P, Martin-Trujillo A, Patel N, Jadhav B, Watson CT, Gibson W, Chetnik K, Tessereau C, Mei H, De Rubeis S, Reichert J, Lopes F, Vissers LELM, Kleefstra T, Grice DE, Edelmann L, Soares G, Maciel P, Brunner HG, Buxbaum JD, Gelb BD, Sharp AJ. Nat Commun 9: 2018 2064	75
A survey of inter-individual variation in DNA methylation identifies environmentally responsive co-regulated networks of epigenetic variation in the human genome. Garg P, Joshi RS, Watson C, Sharp AJ. PLoS Genet 14: 2018 e1007707	44
A compendium of uniformly processed human gene expression and splicing quantitative trait loci. Kerimov N, Hayhurst JD, Peikova K, Manning JR, Walter P, Kolberg L, Samoviča M, Sakthivel MP, Kuzmin I, Trevanion SJ, Burdett T, Jupp S, Parkinson H, Papatheodorou I, Yates AD, Zerbino DR, Alasoo K. Nat Genet 53: 2021 1290-1299	367
Non-coding variants impact cis-regulatory coordination in a cell type-specific manner. Pushkarev O, van Mierlo G, Kribelbauer JF, Saelens W, Gardeux V, Deplancke B. Genome Biol 25: 2024 190	5
Trans-eQTL mapping prioritises USP18 as a negative regulator of interferon response at a lupus risk locus. Freimann K, Brümmer A, Warmerdam R, Rupall TS, Hernández-Ledesma AL, Chiou J, Holzinger ER, Maranville JC, Nakic N, Ongen H, Stefanucci L, Turchin MC, eQTLGen Consortium, Franke L, Võsa U, Jones CP, Medina-Rivera A, Trynka G, Kisand K, Bergmann S, Alasoo K. Nat Commun 16: 2025 8795	1