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

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 methyl...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-09, Vol.114 (36), p.E7526-E7535
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Cell Differentiation - genetics
Cell Line
Chromatin
CpG islands
CpG Islands - genetics
Deoxyribonucleic acid
Differentiation
DNA
DNA methylation
DNA Methylation - genetics
DNA methyltransferase
Epigenesis, Genetic - genetics
Epigenetics
Genome, Human - genetics
Genomes
Humans
Islands
Malignancy
Mice
PNAS Plus
Promoter Regions, Genetic - genetics
Promoters
Sequence Analysis, DNA - methods
Studies
Transcription, Genetic - genetics
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1703087114