DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease

Jeziorska, Danuta M.; Murray, Robert J. S.; De Gobbi, Marco; Gaentzsch, Ricarda; Garrick, David; Ayyub, Helena; Chen, Taiping; Li, En; Telenius, Jelena; Lynch, Magnus; Graham, Bryony; Smith, Andrew J. H.; Lund, Jonathan N.; Hughes, Jim R.; Higgs, Douglas R.; Tufarelli, Cristina

Abstract

The human genome contains ∼30,000 CpG islands (CGIs). While CGIs associated with promoters nearly always remain unmethylated, many of the ∼9,000 CGIs lying within gene bodies become methylated during development and differentiation. Both promoter and intragenic CGIs may also become abnormally methylated as a result of genome rearrangements and in malignancy. The epigenetic mechanisms by which some CGIs become methylated but others, in the same cell, remain unmethylated in these situations are poorly understood. Analyzing specific loci and using a genome-wide analysis, we show that transcription running across CGIs, associated with specific chromatin modifications, is required for DNA methyltransferase 3B (DNMT3B)-mediated DNA methylation of many naturally occurring intragenic CGIs. Importantly, we also show that a subgroup of intragenic CGIs is not sensitive to this process of transcription-mediated methylation and that this correlates with their individual intrinsic capacity to initiate transcription in vivo. We propose a general model of how transcription could act as a primary determinant of the patterns of CGI methylation in normal development and differentiation, and in human disease.

Citation

Jeziorska, D. M., Murray, R. J. S., De Gobbi, M., Gaentzsch, R., Garrick, D., Ayyub, H., …Tufarelli, C. (2017). DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease. Proceedings of the National Academy of Sciences, 114(36), E7526-E7535. https://doi.org/10.1073/pnas.1703087114

• Journal Article Type: Article
• Acceptance Date: Jul 28, 2017
• Online Publication Date: Aug 21, 2017
• Publication Date: Sep 5, 2017
• Deposit Date: Jun 10, 2019
• Publicly Available Date: Jul 29, 2019
• Journal: Proceedings of the National Academy of Sciences
• Print ISSN: 0027-8424
• Electronic ISSN: 1091-6490
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 114
• Issue: 36
• Pages: E7526-E7535
• DOI: https://doi.org/10.1073/pnas.1703087114
• Public URL: https://nottingham-repository.worktribe.com/output/1379490
• Publisher URL: https://www.pnas.org/content/114/36/E7526
• Contract Date: Jul 29, 2019