Species-Specific Relationships between DNA and Chromatin Properties of CpG Islands in Embryonic Stem Cells and Differentiated Cells

Justin Langerman; David Lopez; Matteo Pellegrini; Stephen T Smale

doi:10.1016/j.stemcr.2021.02.016

Species-Specific Relationships between DNA and Chromatin Properties of CpG Islands in Embryonic Stem Cells and Differentiated Cells

Stem Cell Reports. 2021 Apr 13;16(4):899-912. doi: 10.1016/j.stemcr.2021.02.016. Epub 2021 Mar 25.

Authors

Justin Langerman¹, David Lopez², Matteo Pellegrini², Stephen T Smale³

Affiliations

¹ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center, University of California, Los Angeles, CA 90095, USA.
² Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center, University of California, Los Angeles, CA 90095, USA; Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
³ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center, University of California, Los Angeles, CA 90095, USA. Electronic address: smale@mednet.ucla.edu.

Abstract

CpG islands often exhibit low DNA methylation, high histone H3 lysine 4 trimethylation, low nucleosome density, and high DNase I hypersensitivity, yet the rules by which CpG islands are sensed remain poorly understood. In this study, we first evaluated the relationships between the DNA and the chromatin properties of CpG islands in embryonic stem cells using modified bacterial artificial chromosomes. Then, using a bioinformatic approach, we identified strict CpG-island density and length thresholds in mouse embryonic stem and differentiated cells that consistently specify low DNA methylation levels. Surprisingly, the human genome exhibited a dramatically different relationship between DNA properties and DNA methylation levels of CpG islands. Further analysis allowed speculation that this difference is accommodated in part by evolutionary changes in the nucleotide composition of orthologous promoters. Thus, a change in the rules by which CpG-island properties are sensed may have co-evolved with compensatory genome adaptation events during mammalian evolution.

Keywords: CpG islands; DNA methylation; chromatin; embryonic stem cells; epigenetics; evolution; nucleosome; promoters.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Differentiation / genetics*
Chromatin / metabolism*
CpG Islands / genetics*
DNA / metabolism*
DNA Methylation / genetics
Embryonic Development / genetics
Genome, Human
Humans
Mice
Models, Biological
Mouse Embryonic Stem Cells / cytology*
Mouse Embryonic Stem Cells / metabolism*
Nucleotides / genetics
Promoter Regions, Genetic
Species Specificity

Substances

Chromatin
Nucleotides
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding