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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

Authors

Danuta M. Jeziorska

Robert J. S. Murray

Marco De Gobbi

Ricarda Gaentzsch

David Garrick

Helena Ayyub

Taiping Chen

En Li

Jelena Telenius

Magnus Lynch

Bryony Graham

Andrew J. H. Smith

Jim R. Hughes

Douglas R. Higgs

Cristina Tufarelli



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.

Journal Article Type Article
Publication Date Sep 5, 2017
Journal Proceedings of the National Academy of Sciences
Electronic ISSN 1091-6490
Publisher National Academy of Sciences
Peer Reviewed Peer Reviewed
Volume 114
Issue 36
Pages E7526-E7535
APA6 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. doi:10.1073/pnas.1703087114
DOI https://doi.org/10.1073/pnas.1703087114
Publisher URL https://www.pnas.org/content/114/36/E7526

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