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5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging

Nature Neuroscience volume 14, pages 16071616 (2011) | Download Citation

Abstract

DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base that is derived from 5-methylcytosine, accounts for 40% of modified cytosine in the brain and has been implicated in DNA methylation–related plasticity. We mapped 5-hmC genome-wide in mouse hippocampus and cerebellum at three different ages, which allowed us to assess its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We found developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC–regulated regions revealed stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum, we found conserved genomic features of 5-hmC. Finally, we found that 5-hmC levels were inversely correlated with methyl-CpG–binding protein 2 dosage, a protein encoded by a gene in which mutations cause Rett syndrome. These data suggest that 5-hmC–mediated epigenetic modification is critical in neurodevelopment and diseases.

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Acknowledgements

We would like to thank the members of the Jin laboratory for their assistance, and S.T. Warren and C. Strauss for critical reading of the manuscript. H.I. is supported by the Training Program in Human Disease Genetics funded by the US National Institutes of Health (NIH, T32MH087977). L.A.G. is supported by NIH grants CA129831 and CA129831-03S1. C.H. was partially supported by NIH grant GM071440. X.C. was supported by NIH grant GM049245 and is a Georgia Research Alliance Eminent Scholar. M.G. and A.I.L. are partially supported by Emory Alzheimer's Disease Center (P50AG025688). P.J. is supported by NIH grants (NS051630, MH076090 and P50AG025688) and Simons Foundation Autism Research Initiative. P.J. is also the recipient of a Beckman Young Investigator Award, Basil O'Connor Scholar Research Award and Alfred P. Sloan Research Fellow in Neuroscience. This work was supported, in part, by the Emory Genetics Discovery Fund.

Author information

Author notes

    • Keith E Szulwach
    •  & Xuekun Li

    These authors contributed equally to this work.

Affiliations

  1. Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Keith E Szulwach
    • , Xuekun Li
    • , Yujing Li
    • , Hasan Irier
    •  & Peng Jin
  2. Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois, USA.

    • Chun-Xiao Song
    • , Qing Dai
    •  & Chuan He
  3. Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, Georgia, USA.

    • Hao Wu
  4. Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Anup K Upadhyay
    •  & Xiaodong Cheng
  5. Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Marla Gearing
    •  & Allan I Levey
  6. Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois, USA.

    • Aparna Vasanthakumar
    •  & Lucy A Godley
  7. Department of Genetics and Neurology, Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.

    • Qiang Chang

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Contributions

K.E.S., X.L. and P.J. designed the experiments. The experiments were performed by K.E.S., X.L., Y.L., C.-X.S., Q.D., H.I., A.V., L.A.G. and C.H. Data analyses were performed by K.E.S., X.L., H.W., H.I., and P.J. M.G., A.I.L. and Q.C. contributed reagents and tissues. A.K.U. and X.C. were responsible for providing the bacterially purified fragments of Tet1 and Mecp2. K.E.S., X.L. and P.J. wrote the manuscript. All of the authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Peng Jin.

Supplementary information

PDF files

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    Supplementary Text and Figures

    Supplementary Figures 1–12 and Supplementary Tables 1 and 2

Excel files

  1. 1.

    Supplementary Data Set 1

    P7 and 6 week Cerebellum gene expression data

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    Supplementary Data Set 2

    P7 Cerebellum DhMRs

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    Supplementary Data Set 3

    6 week Cerebellum DhMRs

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    Supplementary Data Set 4

    1 year Cerebellum DhMRs

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    Supplementary Data Set 5

    P7 Hippocampus DhMRs

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    Supplementary Data Set 6

    6 week Hippocampus DhMRs

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    Supplementary Data Set 7

    1 year Hippocampus DhMRs

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    Supplementary Data Set 8

    Tissue specific, Stable, and Dynamic DhMRs

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    Supplementary Data Set 9

    GO Analyses

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    Supplementary Data Set 10

    Human 5-hmC enriched regions

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DOI

https://doi.org/10.1038/nn.2959

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