A comprehensive analysis of 195 DNA methylomes reveals shared and cell-specific features of partially methylated domains

Genome Biology - Tập 19 - Trang 1-13 - 2018
Abdulrahman Salhab1, Karl Nordström1, Gilles Gasparoni1, Kathrin Kattler1, Peter Ebert2, Fidel Ramirez3, Laura Arrigoni3, Fabian Müller2, Julia K. Polansky4,5, Cristina Cadenas6, Jan G.Hengstler6, Thomas Lengauer2, Thomas Manke3, Jörn Walter1
1Department of Genetics, Saarland University, Saarbrücken, Germany
2Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Saarbrücken, Germany
3Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
4Berlin-Brandenburg Center for Regenerative Therapies at the Charité, Berlin, Germany
5University Medicine Berlin and German Rheumatism Research Centre, Berlin, Germany
6Leibniz Research Center for Working Environment and Human Factors–IfADo, Dortmund, Germany

Tóm tắt

Partially methylated domains are extended regions in the genome exhibiting a reduced average DNA methylation level. They cover gene-poor and transcriptionally inactive regions and tend to be heterochromatic. We present a comprehensive comparative analysis of partially methylated domains in human and mouse cells, to identify structural and functional features associated with them. Partially methylated domains are present in up to 75% of the genome in human and mouse cells irrespective of their tissue or cell origin. Each cell type has a distinct set of partially methylated domains, and genes expressed in such domains show a strong cell type effect. The methylation level varies between cell types with a more pronounced effect in differentiating and replicating cells. The lowest level of methylation is observed in highly proliferating and immortal cancer cell lines. A decrease of DNA methylation within partially methylated domains tends to be linked to an increase in heterochromatic histone marks and a decrease of gene expression. Characteristic combinations of heterochromatic signatures in partially methylated domains are linked to domains of early and middle S-phase and late S-G2 phases of DNA replication. Partially methylated domains are prominent signatures of long-range epigenomic organization. Integrative analysis identifies them as important general, lineage- and cell type-specific topological features. Changes in partially methylated domains are hallmarks of cell differentiation, with decreased methylation levels and increased heterochromatic marks being linked to enhanced cell proliferation. In combination with broad histone marks, partially methylated domains demarcate distinct domains of late DNA replication.

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