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A comparative analysis of DNA methylation across human embryonic stem cell lines

Pao-Yang Chen12, Suhua Feng1, Jong Wha Joanne Joo3, Steve E Jacobsen145* and Matteo Pellegrini156*

Author affiliations

1 Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA

2 Institute of Genomics and Proteomics, University of California, Los Angeles, CA 90095, USA

3 Interdepartmental Program in Bioinformatics, University of California Los Angeles, Los Angeles, CA 90095, USA

4 Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA

5 Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA

6 Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA

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Citation and License

Genome Biology 2011, 12:R62  doi:10.1186/gb-2011-12-7-r62

Published: 6 July 2011

Abstract

Background

We performed a comparative analysis of the genome-wide DNA methylation profiles from three human embryonic stem cell (HESC) lines. It had previously been shown that HESC lines had significantly higher non-CG methylation than differentiated cells, and we therefore asked whether these sites were conserved across cell lines.

Results

We find that heavily methylated non-CG sites are strongly conserved, especially when found within the motif TACAG. They are enriched in splice sites and are more methylated than other non-CG sites in genes. We next studied the relationship between allele-specific expression and allele-specific methylation. By combining bisulfite sequencing and whole transcriptome shotgun sequencing (RNA-seq) data we identified 1,020 genes that show allele-specific expression, and 14% of CG sites genome-wide have allele-specific methylation. Finally, we asked whether the methylation state of transcription factor binding sites affects the binding of transcription factors. We identified variations in methylation levels at binding sites and found that for several transcription factors the correlation between the methylation at binding sites and gene expression is generally stronger than in the neighboring sequences.

Conclusions

These results suggest a possible but as yet unknown functional role for the highly methylated conserved non-CG sites in the regulation of HESCs. We also identified a novel set of genes that are likely transcriptionally regulated by methylation in an allele-specific manner. The analysis of transcription factor binding sites suggests that the methylation state of cis-regulatory elements impacts the ability of factors to bind and regulate transcription.