PUBLICATION
Protection of CpG islands from DNA methylation is DNA-encoded and evolutionarily conserved
- Authors
- Long, H.K., King, H.W., Patient, R.K., Odom, D.T., Klose, R.J.
- ID
- ZDB-PUB-160417-3
- Date
- 2016
- Source
- Nucleic acids research 44(14): 6693-706 (Journal)
- Registered Authors
- Patient, Roger K.
- Keywords
- none
- Datasets
- GEO:GSE43512, GEO:GSE72208
- MeSH Terms
-
- Animals
- Cell Line
- Chromosomes, Human, Pair 21/genetics
- Conserved Sequence/genetics*
- CpG Islands/genetics*
- DNA/genetics*
- DNA Methylation/genetics*
- Evolution, Molecular*
- Female
- Gene Expression Regulation
- Humans
- Male
- Mice, Inbred C57BL
- Mice, Transgenic
- Promoter Regions, Genetic
- Protein Binding/genetics
- Repetitive Sequences, Nucleic Acid/genetics
- Species Specificity
- Transcription Factors/metabolism
- Vertebrates/genetics
- PubMed
- 27084945 Full text @ Nucleic Acids Res.
Citation
Long, H.K., King, H.W., Patient, R.K., Odom, D.T., Klose, R.J. (2016) Protection of CpG islands from DNA methylation is DNA-encoded and evolutionarily conserved. Nucleic acids research. 44(14):6693-706.
Abstract
DNA methylation is a repressive epigenetic modification that covers vertebrate genomes. Regions known as CpG islands (CGIs), which are refractory to DNA methylation, are often associated with gene promoters and play central roles in gene regulation. Yet how CGIs in their normal genomic context evade the DNA methylation machinery and whether these mechanisms are evolutionarily conserved remains enigmatic. To address these fundamental questions we exploited a transchromosomic animal model and genomic approaches to understand how the hypomethylated state is formedin vivoand to discover whether mechanisms governing CGI formation are evolutionarily conserved. Strikingly, insertion of a human chromosome into mouse revealed that promoter-associated CGIs are refractory to DNA methylation regardless of host species, demonstrating that DNA sequence plays a central role in specifying the hypomethylated state through evolutionarily conserved mechanisms. In contrast, elements distal to gene promoters exhibited more variable methylation between host species, uncovering a widespread dependence on nucleotide frequency and occupancy of DNA-binding transcription factors in shaping the DNA methylation landscape away from gene promoters. This was exemplified by young CpG rich lineage-restricted repeat sequences that evaded DNA methylation in the absence of co-evolved mechanisms targeting methylation to these sequences, and species specific DNA binding events that protected against DNA methylation in CpG poor regions. Finally, transplantation of mouse chromosomal fragments into the evolutionarily distant zebrafish uncovered the existence of a mechanistically conserved and DNA-encoded logic which shapes CGI formation across vertebrate species.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping