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Developmental programming of CpG island methylation profiles in the human genome

Nature Structural & Molecular Biology volume 16, pages 564–571 (2009)Cite this article

Abstract

CpG island–like sequences are commonly thought to provide the sole signals for designating constitutively unmethylated regions in the genome, thus generating open chromatin domains within a sea of global repression. Using a new database obtained from comprehensive microarray analysis, we show that unmethylated regions (UMRs) seem to be formed during early embryogenesis, not as a result of CpG-ness, but rather through the recognition of specific sequence motifs closely associated with transcription start sites. This same system probably brings about the resetting of pluripotency genes during somatic cell reprogramming. The data also reveal a new class of nonpromoter UMRs that become de novo methylated in a tissue-specific manner during development, and this process may be involved in gene regulation. In short, we show that UMRs are an important aspect of genome structure that have a dynamic role in development.

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Figure 1: Detection of methylation by mDIP microarray analysis.
Figure 2: Methylated and unmethylated islands.
Figure 3: Unmethylated CpG islands have TSSs.
Figure 4: CpG island sequence motifs.
Figure 5: Tissue-specific de novo methylation.

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Acknowledgements

This work was supported by the Israel Cancer Research Fund (H.C.), the Rosetrees Trust (H.C.), Lewis Sanders (H.C.), both Philip Morris USA Inc. and Philip Morris International (R.S.) and an Agilent University Relations grant (H.C.).

Author information

Author notes

  1. Ravid Straussman

    Present address: Present address: The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.,

Authors and Affiliations

  1. Department of Cellular Biochemistry and Human Genetics, The Hebrew University–Hadassah Medical School, Jerusalem, Israel

    Ravid Straussman, Deborah Nejman & Howard Cedar

  2. Agilent Technologies Inc., Santa Clara, California, USA

    Douglas Roberts

  3. Agilent Laboratories, Tel Aviv, Israel

    Israel Steinfeld & Zohar Yakhini

  4. Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem, Israel

    Barak Blum & Nissim Benvenisty

  5. Department of Molecular Biology, The Hebrew University–Hadassah Medical School, Jerusalem, Israel

    Itamar Simon

  6. Department of Computer Sciences, Technion–Israel Institute of Technology, Haifa, Israel

    Zohar Yakhini

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Contributions

R.S. and D.N. carried out all mDIP, bisulfite and transfection experiments and did most of the data analysis; D.R. and R.S. performed all of the labeling and microarray hybridizations; I.St., Z.Y. and I.Si. were responsible for all the computational biology including the development of algorithms; B.B. and N.B. prepared the DNA from human ES cells; R.S. managed and organized all of the experimental work and generated the main concepts; H.C. wrote the manuscript and contributed to the design and interpretation of all experiments.

Corresponding author

Correspondence to Howard Cedar.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Methods (PDF 2430 kb)

Supplementary Table 1

CpG island methylation data (XLS 14692 kb)

Supplementary Table 2

CpG island methylation data – BED file for UCSC upload (TXT 3949 kb)

Supplementary Table 3

Sequence motifs enriched in unmethylated islands (PDF 35 kb)

Supplementary Table 4

Prediction of unmethylated CpG islands (PDF 32 kb)

Supplementary Table 5

UMR methylation data (XLS 1710 kb)

Supplementary Table 6

Non-CpG island housekeeping gene promoters (PDF 81 kb)

Supplementary Table 7

Intragenic methylation and GO analysis of Refseq genes with internal islands (PDF 66 kb)

Supplementary Table 8

Comparison of published results estimating the percentage of methylated CpG islands in the Human genome (PDF 51 kb)

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Straussman, R., Nejman, D., Roberts, D. et al. Developmental programming of CpG island methylation profiles in the human genome. Nat Struct Mol Biol 16, 564–571 (2009). https://doi.org/10.1038/nsmb.1594

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