Consistent inverse correlation between DNA methylation of the first intron and gene expression across tissues and species

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• dc.contributor.author Anastasiadi, Dafni, 1986-
• dc.contributor.author Esteve-Codina, Anna
• dc.contributor.author Piferrer, Francesc
• dc.date.accessioned 2019-11-14T13:24:38Z
• dc.date.available 2019-11-14T13:24:38Z
• dc.date.issued 2018
• dc.description.abstract Background: DNA methylation is one of the main epigenetic mechanisms for the regulation of gene expression in eukaryotes. In the standard model, methylation in gene promoters has received the most attention since it is generally associated with transcriptional silencing. Nevertheless, recent studies in human tissues reveal that methylation of the region downstream of the transcription start site is highly informative of gene expression. Also, in some cell types and specific genes it has been found that methylation of the first intron, a gene feature typically rich in enhancers, is linked with gene expression. However, a genome-wide, tissue-independent, systematic comparative analysis of the relationship between DNA methylation in the first intron and gene expression across vertebrates has not been explored yet. Results: The most important findings of this study are: (1) using different tissues from a modern fish, we show a clear genome-wide, tissue-independent quasi-linear inverse relationship between DNA methylation of the first intron and gene expression. (2) This relationship is conserved across vertebrates, since it is also present in the genomes of a model pufferfish, a model frog and different human tissues. Among the gene features, tissues and species interrogated, the first intron’s negative correlation with the gene expression was most consistent. (3) We identified more tissue-specific differentially methylated regions (tDMRs) in the first intron than in any other gene feature. These tDMRs have positive or negative correlation with gene expression, indicative of distinct mechanisms of tissue-specific regulation. (4) Lastly, we identified CpGs in transcription factor binding motifs, enriched in the first intron, the methylation of which tended to increase with the distance from the first exon–first intron boundary, with a concomitant decrease in gene expression. Conclusions: Our integrative analysis clearly reveals the important and conserved role of the methylation level of the first intron and its inverse association with gene expression regardless of tissue and species. These findings not only contribute to our basic understanding of the epigenetic regulation of gene expression but also identify the first intron as an informative gene feature regarding the relationship between DNA methylation and gene expression where future studies should be focused.
• dc.description.sponsorship DA was supported by a Ph.D. scholarship from the Spanish Government (BES–2011–044860). AEC is funded by the RED-BIO project of the Spanish National Bioinformatics Institute (INB) under grant number PT13/0001/0044. The INB is funded by the Spanish National Health Institute Carlos III (ISCIII) and the Spanish Ministry of Economy and Competitiveness (MINECO). Research supported by MINECO grant “Epifarm” (ref. AGL2013–41047–R) to FP. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).
• dc.format.mimetype application/pdf
• dc.identifier.citation Anastasiadi D, Esteve-Codina A, Piferrer F. Consistent inverse correlation between DNA methylation of the first intron and gene expression across tissues and species. Epigenetics Chromatin. 2018;11(1):37. DOI: 10.1186/s13072-018-0205-1
• dc.identifier.doi http://dx.doi.org/10.1186/s13072-018-0205-1
• dc.identifier.issn 1756-8935
• dc.identifier.uri http://hdl.handle.net/10230/42850
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Epigenetics & Chromatin. 2018;11(1):37
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BES–2011–044860
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/AGL2013–41047–R
• dc.rights © The Author(s) 2018. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword DNA methylation
• dc.subject.keyword First intron
• dc.subject.keyword Gene expression
• dc.subject.keyword Gene features
• dc.subject.keyword Regulation
• dc.title Consistent inverse correlation between DNA methylation of the first intron and gene expression across tissues and species
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion