Replication timing-related and gene body-specific methylation of active human genes

Dvir Aran, Gidon Toperoff, Michael Rosenberg, Asaf Hellman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

218 Scopus citations

Abstract

Understanding how the epigenetic blueprint of the genome shapes human phenotypes requires systematic evaluation of the complex interplay between gene activity and the different layers of the epigenome. Utilizing microarray-based techniques, we explored the relationships between DNA methylation, DNA replication timing and gene expression levels across a variety of human tissues and cell lines. The analyses revealed unequal methylation levels among early- and late-replicating fractions of the genome: late-replicating DNA was hypomethylated compared with early-replicating DNA. Moreover, late-replicating regions were gradually demethylated with cell divisions, whereas the methylation of early-replicating regions was better maintained. As active genes concentrate at early-replicating regions, they are overall hypermethylated relative to inactive genes. Accordingly, we show that the previously reported positive correlation between gene-body methylation (methylation of the transcribed portion of genes) and gene expression is restricted to proliferative tissues and cell lines, whereas in tissues containing few proliferating cells, active and inactive genes have similar methylation levels. We further show that active gene bodies are hypermethylated not only compared with inactive gene bodies, but also compared with their flanking sequences. This specific hypermethylation of the active gene bodies is severely disrupted in cells of an immunodeficiency, centromeric region instability, facial anomalies (ICF) syndrome patient bearing mutated DNA methyltransferase 3B (DNMT3B). Our data show that a high methylation level is preferentially maintained in active gene bodies through independent cellular processes. Rather than serving as a distinctive mark between active and inactive genes, gene-body methylation appears to serve a vital, currently unknown function in active genes.

Original languageAmerican English
Article numberddq513
Pages (from-to)670-680
Number of pages11
JournalHuman Molecular Genetics
Volume20
Issue number4
DOIs
StatePublished - Feb 2011

Bibliographical note

Funding Information:
This work was supported by the Israel Science Foundation grant number 887/08 to A.H. and by the Israel Cancer Research Fund grant number 08-716-RCDA to A.H.

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