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Open Access Highly Accessed Research article

Genome-wide survey reveals dynamic widespread tissue-specific changes in DNA methylation during development

Ping Liang1*, Fei Song23, Srimoyee Ghosh45, Evan Morien46, Maochun Qin4, Saleh Mahmood27, Kyoko Fujiwara48, Jun Igarashi8, Hiroki Nagase489* and William A Held2

Author Affiliations

1 Department of Biological Sciences, Brock University, St. Catharines, Ontario, Canada

2 Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA

3 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA

4 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA

5 Department of Zoology, North-Eastern Hill University, Umshing Mawkynroh, Shillong, Meghalaya, India

6 Department of Bioinformatics, University of British Columbia, Vancouver, British Columbia, Canada

7 Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, USA

8 Division of Cancer Genetics, Department of Advanced Medical Science, Nihon University School of Medicine, Tokyo, Japan

9 Division of Cancer Genetics, Chiba Cancer Center, Research Institute, Chiba, Japan

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BMC Genomics 2011, 12:231  doi:10.1186/1471-2164-12-231

Published: 11 May 2011

Abstract

Background

Changes in DNA methylation in the mammalian genome during development are frequent events and play major roles regulating gene expression and other developmental processes. It is necessary to identify these events so that we may understand how these changes affect normal development and how aberrant changes may impact disease.

Results

In this study

    Me
thylated
    D
NA
    I
mmuno
    P
recipitation (MeDIP) was used in conjunction with a NimbleGen promoter plus CpG island (CpGi) array to identify
    T
issue and
    D
evelopmental
    S
tage specific
    D
ifferentially
    M
ethylated DNA
    R
egions (T-DMRs and DS-DMRs) on a genome-wide basis. Four tissues (brain, heart, liver, and testis) from C57BL/6J mice were analyzed at three developmental stages (15 day embryo, E15; new born, NB; 12 week adult, AD). Almost 5,000 adult T-DMRs and 10,000 DS-DMRs were identified. Surprisingly, almost all DS-DMRs were tissue specific (i.e. methylated in at least one tissue and unmethylated in one or more tissues). In addition our results indicate that many DS-DMRs are methylated at early development stages (E15 and NB) but are unmethylated in adult. There is a very strong bias for testis specific methylation in non-CpGi promoter regions (94%). Although the majority of T-DMRs and DS-DMRs tended to be in non-CpGi promoter regions, a relatively large number were also located in CpGi in promoter, intragenic and intergenic regions (>15% of the 15,979 CpGi on the array).

Conclusions

Our data suggests the vast majority of unique sequence DNA methylation has tissue specificity, that demethylation has a prominent role in tissue differentiation, and that DNA methylation has regulatory roles in alternative promoter selection and in non-promoter regions. Overall, our studies indicate changes in DNA methylation during development are a dynamic, widespread, and tissue-specific process involving both DNA methylation and demethylation.