Dataset Information

Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells.

ABSTRACT: Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.

SUBMITTER: Chen L

PROVIDER: S-EPMC5119954 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells.

Chen Lu L Ge Bing B Casale Francesco Paolo FP Vasquez Louella L Kwan Tony T Garrido-Martín Diego D Watt Stephen S Yan Ying Y Kundu Kousik K Ecker Simone S Datta Avik A Richardson David D Burden Frances F Mead Daniel D Mann Alice L AL Fernandez Jose Maria JM Rowlston Sophia S Wilder Steven P SP Farrow Samantha S Shao Xiaojian X Lambourne John J JJ Redensek Adriana A Albers Cornelis A CA Amstislavskiy Vyacheslav V Ashford Sofie S Berentsen Kim K Bomba Lorenzo L Bourque Guillaume G Bujold David D Busche Stephan S Caron Maxime M Chen Shu-Huang SH Cheung Warren W Delaneau Oliver O Dermitzakis Emmanouil T ET Elding Heather H Colgiu Irina I Bagger Frederik O FO Flicek Paul P Habibi Ehsan E Iotchkova Valentina V Janssen-Megens Eva E Kim Bowon B Lehrach Hans H Lowy Ernesto E Mandoli Amit A Matarese Filomena F Maurano Matthew T MT Morris John A JA Pancaldi Vera V Pourfarzad Farzin F Rehnstrom Karola K Rendon Augusto A Risch Thomas T Sharifi Nilofar N Simon Marie-Michelle MM Sultan Marc M Valencia Alfonso A Walter Klaudia K Wang Shuang-Yin SY Frontini Mattia M Antonarakis Stylianos E SE Clarke Laura L Yaspo Marie-Laure ML Beck Stephan S Guigo Roderic R Rico Daniel D Martens Joost H A JHA Ouwehand Willem H WH Kuijpers Taco W TW Paul Dirk S DS Stunnenberg Hendrik G HG Stegle Oliver O Downes Kate K Pastinen Tomi T Soranzo Nicole N

Cell 20161101 5

Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcript ...[more]

PMID: 27863251

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Project description:Natural plant populations often harbour substantial heritable variation in DNA methylation. However, a thorough understanding of the genetic and environmental drivers of this epigenetic variation requires large-scale and high-resolution data, which currently exist only for a few model species. Here, we studied 207 lines of the annual weed Thlaspi arvense (field pennycress), collected across a large latitudinal gradient in Europe and propagated in a common environment. By screening for variation in DNA sequence and DNA methylation using whole-genome (bisulfite) sequencing, we found significant epigenetic population structure across Europe. Average levels of DNA methylation were strongly context-dependent, with highest DNA methylation in CG context, particularly in transposable elements and in intergenic regions. Residual DNA methylation variation within all contexts was associated with genetic variants, which often co-localized with annotated methylation machinery genes but also with new candidates. Variation in DNA methylation was also significantly associated with climate of origin, with methylation levels being lower in colder regions and in more variable climates. Finally, we used variance decomposition to assess genetic versus environmental associations with differentially methylated regions (DMRs). We found that while genetic variation was generally the strongest predictor of DMRs, the strength of environmental associations increased from CG to CHG and CHH, with climate-of-origin as the strongest predictor in about one third of the CHH DMRs. In summary, our data show that natural epigenetic variation in Thlaspi arvense is significantly associated with both DNA sequence and environment of origin, and that the relative importance of the two factors strongly depends on the sequence context of DNA methylation. T. arvense is an emerging biofuel and winter cover crop; our results may hence be relevant for breeding efforts and agricultural practices in the context of rapidly changing environmental conditions.

Dataset Information

Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells.

Publications

Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells.

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