Journal Article
. 2015 Jan; 11(1):e1004958.
doi: 10.1371/journal.pgen.1004958.

Tissue-specific effects of genetic and epigenetic variation on gene regulation and splicing

Maria Gutierrez-Arcelus 1 Halit Ongen 1 Tuuli Lappalainen 1 Stephen B Montgomery 2 Alfonso Buil 1 Alisa Yurovsky 1 Julien Bryois 1 Ismael Padioleau 1 Luciana Romano 1 Alexandra Planchon 1 Emilie Falconnet 3 Deborah Bielser 3 Maryline Gagnebin 3 Thomas Giger 4 Christelle Borel 4 Audrey Letourneau 3 Periklis Makrythanasis 3 Michel Guipponi 3 Corinne Gehrig 3 Stylianos E Antonarakis 3 Emmanouil T Dermitzakis 5 
Affiliations
  • PMID: 25634236
  •     66 References
  •     82 citations

Abstract

Understanding how genetic variation affects distinct cellular phenotypes, such as gene expression levels, alternative splicing and DNA methylation levels, is essential for better understanding of complex diseases and traits. Furthermore, how inter-individual variation of DNA methylation is associated to gene expression is just starting to be studied. In this study, we use the GenCord cohort of 204 newborn Europeans' lymphoblastoid cell lines, T-cells and fibroblasts derived from umbilical cords. The samples were previously genotyped for 2.5 million SNPs, mRNA-sequenced, and assayed for methylation levels in 482,421 CpG sites. We observe that methylation sites associated to expression levels are enriched in enhancers, gene bodies and CpG island shores. We show that while the correlation between DNA methylation and gene expression can be positive or negative, it is very consistent across cell-types. However, this epigenetic association to gene expression appears more tissue-specific than the genetic effects on gene expression or DNA methylation (observed in both sharing estimations based on P-values and effect size correlations between cell-types). This predominance of genetic effects can also be reflected by the observation that allele specific expression differences between individuals dominate over tissue-specific effects. Additionally, we discover genetic effects on alternative splicing and interestingly, a large amount of DNA methylation correlating to alternative splicing, both in a tissue-specific manner. The locations of the SNPs and methylation sites involved in these associations highlight the participation of promoter proximal and distant regulatory regions on alternative splicing. Overall, our results provide high-resolution analyses showing how genome sequence variation has a broad effect on cellular phenotypes across cell-types, whereas epigenetic factors provide a secondary layer of variation that is more tissue-specific. Furthermore, the details of how this tissue-specificity may vary across inter-relations of molecular traits, and where these are occurring, can yield further insights into gene regulation and cellular biology as a whole.

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Principles and methods of in-silico prioritization of non-coding regulatory variants.
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Hum Genet, 2017 Dec 31; 137(1). PMID: 29288389    Free PMC article.
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Integrative transcriptome sequencing reveals extensive alternative trans-splicing and cis-backsplicing in human cells.
Trees-Juen Chuang, Yen-Ju Chen, +14 authors, Tai-Wei Chiang.
Nucleic Acids Res, 2018 Feb 01; 46(7). PMID: 29385530    Free PMC article.
Characterization of cross-tissue genetic-epigenetic effects and their patterns in schizophrenia.
Dongdong Lin, Jiayu Chen, +4 authors, Jingyu Liu.
Genome Med, 2018 Feb 28; 10(1). PMID: 29482655    Free PMC article.
Distinct chromatin signatures of DNA hypomethylation in aging and cancer.
Raúl F Pérez, Juan Ramón Tejedor, +2 authors, Mario F Fraga.
Aging Cell, 2018 Mar 06; 17(3). PMID: 29504244    Free PMC article.
A mega-analysis of expression quantitative trait loci (eQTL) provides insight into the regulatory architecture of gene expression variation in liver.
Tobias Strunz, Felix Grassmann, +6 authors, Bernhard H F Weber.
Sci Rep, 2018 Apr 14; 8(1). PMID: 29650998    Free PMC article.
Opposite Effects of Two Human ATG10 Isoforms on Replication of a HCV Sub-genomic Replicon Are Mediated via Regulating Autophagy Flux in Zebrafish.
Yu-Chen Li, Miao-Qing Zhang, Jing-Pu Zhang.
Front Cell Infect Microbiol, 2018 Apr 20; 8. PMID: 29670865    Free PMC article.
High sensitivity and label-free oligonucleotides detection using photonic bandgap sensing structures biofunctionalized with molecular beacon probes.
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Biomed Opt Express, 2018 Apr 21; 9(4). PMID: 29675313    Free PMC article.
Bioinformatics challenges and perspectives when studying the effect of epigenetic modifications on alternative splicing.
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Philos Trans R Soc Lond B Biol Sci, 2018 Apr 25; 373(1748). PMID: 29685977    Free PMC article.
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Genomic approaches for the elucidation of genes and gene networks underlying cardiovascular traits.
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Biophys Rev, 2018 Jun 24; 10(4). PMID: 29934864    Free PMC article.
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Allele-specific epigenome maps reveal sequence-dependent stochastic switching at regulatory loci.
Vitor Onuchic, Eugene Lurie, +16 authors, Aleksandar Milosavljevic.
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DNA Methylation Profiles in Whole Blood of Huntington's Disease Patients.
Maja Zadel, Aleš Maver, Anja Kovanda, Borut Peterlin.
Front Neurol, 2018 Aug 31; 9. PMID: 30158895    Free PMC article.
Environmental influences on RNA processing: Biochemical, molecular and genetic regulators of cellular response.
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Wiley Interdiscip Rev RNA, 2018 Sep 15; 10(1). PMID: 30216698    Free PMC article.
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Large-scale transcriptome-wide association study identifies new prostate cancer risk regions.
Nicholas Mancuso, Simon Gayther, +8 authors, PRACTICAL consortium.
Nat Commun, 2018 Oct 06; 9(1). PMID: 30287866    Free PMC article.
Integration of methylation QTL and enhancer-target gene maps with schizophrenia GWAS summary results identifies novel genes.
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Bioinformatics, 2019 Mar 10; 35(19). PMID: 30850848    Free PMC article.
More than a messenger: Alternative splicing as a therapeutic target.
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Biochim Biophys Acta Gene Regul Mech, 2019 Jul 05; 1862(11-12). PMID: 31271898    Free PMC article.
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A secreted microRNA disrupts autophagy in distinct tissues of Caenorhabditis elegans upon ageing.
Yifei Zhou, Xueqing Wang, +7 authors, Yidong Shen.
Nat Commun, 2019 Oct 28; 10(1). PMID: 31645592    Free PMC article.
The exploration of disease-specific gene regulatory networks in esophageal carcinoma and stomach adenocarcinoma.
Guimin Qin, Luqiong Yang, +2 authors, Qiuyan Huo.
BMC Bioinformatics, 2020 Jan 01; 20(Suppl 22). PMID: 31888440    Free PMC article.
Large epigenome-wide association study of childhood ADHD identifies peripheral DNA methylation associated with disease and polygenic risk burden.
Michael A Mooney, Peter Ryabinin, +3 authors, Joel T Nigg.
Transl Psychiatry, 2020 Feb 19; 10(1). PMID: 32066674    Free PMC article.
IGREX for quantifying the impact of genetically regulated expression on phenotypes.
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The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region.
Nora Fernandez-Jimenez, Koldo Garcia-Etxebarria, +12 authors, Jose Ramon Bilbao.
Sci Rep, 2019 Feb 06; 9(1). PMID: 30718669    Free PMC article.
Exploring the influence from whole blood DNA extraction methods on Infinium 450K DNA methylation.
Hanne Sagsveen Hjorthaug, Kristina Gervin, Petter Mowinckel, Monica Cheng Munthe-Kaas.
PLoS One, 2018 Dec 13; 13(12). PMID: 30540848    Free PMC article.
Exploring the genetic basis of human population differences in DNA methylation and their causal impact on immune gene regulation.
Lucas T Husquin, Maxime Rotival, +8 authors, Lluis Quintana-Murci.
Genome Biol, 2018 Dec 20; 19(1). PMID: 30563547    Free PMC article.
Integration of DNA methylation patterns and genetic variation in human pediatric tissues help inform EWAS design and interpretation.
Sumaiya A Islam, Sarah J Goodman, +4 authors, Michael S Kobor.
Epigenetics Chromatin, 2019 Jan 04; 12(1). PMID: 30602389    Free PMC article.
Longitudinal genome-wide DNA methylation analysis uncovers persistent early-life DNA methylation changes.
Raúl F Pérez, Pablo Santamarina, +6 authors, Empar Lurbe.
J Transl Med, 2019 Jan 11; 17(1). PMID: 30626398    Free PMC article.
Integrative analysis of DNA methylation in discordant twins unveils distinct architectures of systemic sclerosis subsets.
Paula S Ramos, Kip D Zimmerman, +3 authors, Carol A Feghali-Bostwick.
Clin Epigenetics, 2019 Apr 06; 11(1). PMID: 30947741    Free PMC article.
Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians.
Yang Luo, Sara Suliman, +18 authors, Soumya Raychaudhuri.
Nat Commun, 2019 Aug 23; 10(1). PMID: 31434886    Free PMC article.
Collective effects of long-range DNA methylations predict gene expressions and estimate phenotypes in cancer.
Soyeon Kim, Hyun Jung Park, Xiangqin Cui, Degui Zhi.
Sci Rep, 2020 Mar 05; 10(1). PMID: 32127627    Free PMC article.
Multi-omics integrative analysis identified SNP-methylation-mRNA: Interaction in peripheral blood mononuclear cells.
Yi-Hua Lu, Bing-Hua Wang, +6 authors, Shu-Feng Lei.
J Cell Mol Med, 2019 May 21; 23(7). PMID: 31106970    Free PMC article.
Lymphocyte DNA methylation mediates genetic risk at shared immune-mediated disease loci.
Alexander D Clark, Nisha Nair, +9 authors, Louise N Reynard.
J Allergy Clin Immunol, 2020 Jan 17; 145(5). PMID: 31945409    Free PMC article.
Transcript specific regulation of expression influences susceptibility to multiple sclerosis.
Maria Ban, Wenjia Liao, +8 authors, Stephen Sawcer.
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sn-spMF: matrix factorization informs tissue-specific genetic regulation of gene expression.
Yuan He, Surya B Chhetri, +9 authors, Alexis Battle.
Genome Biol, 2020 Sep 12; 21(1). PMID: 32912314    Free PMC article.
Alternative splicing of MR1 regulates antigen presentation to MAIT cells.
Gitanjali A Narayanan, Abhinav Nellore, +8 authors, David M Lewinsohn.
Sci Rep, 2020 Sep 24; 10(1). PMID: 32963314    Free PMC article.
Association of CNVs with methylation variation.
Xinghua Shi, Saranya Radhakrishnan, +7 authors, Sunita R Setlur.
NPJ Genom Med, 2020 Oct 17; 5. PMID: 33062306    Free PMC article.
Expression Quantitative Trait Methylation Analysis Reveals Methylomic Associations With Gene Expression in Childhood Asthma.
Soyeon Kim, Erick Forno, +8 authors, Juan C Celedón.
Chest, 2020 Jun 23; 158(5). PMID: 32569636    Free PMC article.
A case-control study on the SNP309T → G and 40-bp Del1518 of the MDM2 gene and a systematic review for MDM2 polymorphisms in the patients with breast cancer.
Amin Jalilvand, Kheirollah Yari, +3 authors, Pantea Mohammadi.
J Clin Lab Anal, 2020 Sep 21; 34(12). PMID: 32951271    Free PMC article.
Profiling Novel Alternative Splicing within Multiple Tissues Provides Useful Insights into Porcine Genome Annotation.
Wen Feng, Pengju Zhao, +2 authors, Jianfeng Liu.
Genes (Basel), 2020 Dec 02; 11(12). PMID: 33255998    Free PMC article.
Defining the genetic and evolutionary architecture of alternative splicing in response to infection.
Maxime Rotival, Hélène Quach, Lluis Quintana-Murci.
Nat Commun, 2019 Apr 13; 10(1). PMID: 30975994    Free PMC article.
Differential DNA Methylation Landscape in Skin Fibroblasts from African Americans with Systemic Sclerosis.
DeAnna Baker Frost, Willian da Silveira, +9 authors, Paula S Ramos.
Genes (Basel), 2021 Jan 28; 12(2). PMID: 33498390    Free PMC article.
Allele-specific expression: applications in cancer and technical considerations.
Carla Daniela Robles-Espinoza, Pejman Mohammadi, Ximena Bonilla, Maria Gutierrez-Arcelus.
Curr Opin Genet Dev, 2021 Jan 01; 66. PMID: 33383480    Free PMC article.
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MOSTWAS: Multi-Omic Strategies for Transcriptome-Wide Association Studies.
Arjun Bhattacharya, Yun Li, Michael I Love.
PLoS Genet, 2021 Mar 09; 17(3). PMID: 33684137    Free PMC article.