The Temporal Order of DNA Replication Shaped by Mammalian DNA Methyltransferases
Open Access
- 28 January 2021
- Vol. 10 (2), 266
- https://doi.org/10.3390/cells10020266
Abstract
Multiple epigenetic pathways underlie the temporal order of DNA replication (replication timing) in the contexts of development and disease. DNA methylation by DNA methyltransferases (Dnmts) and downstream chromatin reorganization and transcriptional changes are thought to impact DNA replication, yet this remains to be comprehensively tested. Using cell-based and genome-wide approaches to measure replication timing, we identified a number of genomic regions undergoing subtle but reproducible replication timing changes in various Dnmt-mutant mouse embryonic stem (ES) cell lines that included a cell line with a drug-inducible Dnmt3a2 expression system. Replication timing within pericentromeric heterochromatin (PH) was shown to be correlated with redistribution of H3K27me3 induced by DNA hypomethylation: Later replicating PH coincided with H3K27me3-enriched regions. In contrast, this relationship with H3K27me3 was not evident within chromosomal arm regions undergoing either early-to-late (EtoL) or late-to-early (LtoE) switching of replication timing upon loss of the Dnmts. Interestingly, Dnmt-sensitive transcriptional up- and downregulation frequently coincided with earlier and later shifts in replication timing of the chromosomal arm regions, respectively. Our study revealed the previously unrecognized complex and diverse effects of the Dnmts loss on the mammalian DNA replication landscape.Keywords
Funding Information
- Ministry of Education, Culture, Sports, Science and Technology of Japan (16H01405 and 20H05386)
This publication has 58 references indexed in Scilit:
- FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditureNature Communications, 2012
- Late-replicating heterochromatin is characterized by decreased cytosine methylation in the human genomeGenome Research, 2011
- Regulation of mammalian DNA methyltransferases: a route to new mechanismsEMBO Reports, 2011
- Genome-scale analysis of replication timing: from bench to bioinformaticsNature Protocols, 2011
- Establishing, maintaining and modifying DNA methylation patterns in plants and animalsNature Reviews Genetics, 2010
- Rethinking how DNA methylation patterns are maintainedNature Reviews Genetics, 2009
- DNA methylation regulates long-range gene silencing of an X-linked homeobox gene cluster in a lineage-specific mannerGenes & Development, 2006
- Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instabilityOncogene, 2006
- Partitioning and Plasticity of Repressive Histone Methylation States in Mammalian ChromatinMolecular Cell, 2003
- Identification of a mammalian protein that binds specifically to DNA containing methylated CpGsCell, 1989