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

Nature Neuroscience volume 14, pages 1607–1616 (2011)Cite this article

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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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Figure 1: Immunostaining, quantification, and genomic mapping of 5-hmC across three ages and two brain regions in mouse.
Figure 2: Identification and characterization of DhMRs.
Figure 3: Dynamic and stable 5-hmC DhMRs in cerebellum and hippocampus.
Figure 4: Analysis of repeat-associated 5-hmC.
Figure 5: Conserved features of 5-hmC in human cerebellum.
Figure 6: Altered 5-hmC states in mouse models of Rett syndrome.

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References

  1. Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33 (suppl.). 245–254 (2003).

    Article  CAS  Google Scholar 

  2. Ito, S. et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466, 1129–1133 (2010).

    Article  CAS  Google Scholar 

  3. Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).

    Article  CAS  Google Scholar 

  4. Valinluck, V. et al. Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res. 32, 4100–4108 (2004).

    Article  CAS  Google Scholar 

  5. Ko, M. et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468, 839–843 (2010).

    Article  CAS  Google Scholar 

  6. Koh, K.P. et al. Tet1 and tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8, 200–213 (2011).

    Article  CAS  Google Scholar 

  7. Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate–dependent dioxygenases. Cancer Cell 19, 17–30 (2011).

    Article  CAS  Google Scholar 

  8. Figueroa, M.E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

    Article  CAS  Google Scholar 

  9. Ficz, G. et al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473, 398–402 (2011).

    Article  CAS  Google Scholar 

  10. Song, C.X. et al. Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat. Biotechnol. 29, 68–72 (2011).

    Article  CAS  Google Scholar 

  11. Williams, K. et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473, 343–348 (2011).

    Article  CAS  Google Scholar 

  12. Wu, H. et al. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev. 25, 679–684 (2011).

    Article  CAS  Google Scholar 

  13. Chen, W.G. et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885–889 (2003).

    Article  CAS  Google Scholar 

  14. Ma, D.K. et al. Neuronal activity–induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323, 1074–1077 (2009).

    Article  CAS  Google Scholar 

  15. Martinowich, K. et al. DNA methylation–related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302, 890–893 (2003).

    Article  CAS  Google Scholar 

  16. Day, J.J. & Sweatt, J.D. DNA methylation and memory formation. Nat. Neurosci. 13, 1319–1323 (2010).

    Article  CAS  Google Scholar 

  17. Miller, C.A. & Sweatt, J.D. Covalent modification of DNA regulates memory formation. Neuron 53, 857–869 (2007).

    Article  CAS  Google Scholar 

  18. Muotri, A.R. et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 468, 443–446 (2010).

    Article  CAS  Google Scholar 

  19. Skene, P.J. et al. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457–468 (2010).

    Article  CAS  Google Scholar 

  20. Riccio, A. Dynamic epigenetic regulation in neurons: enzymes, stimuli and signaling pathways. Nat. Neurosci. 13, 1330–1337 (2010).

    Article  CAS  Google Scholar 

  21. Globisch, D. et al. Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates. PLoS ONE 5, e15367 (2010).

    Article  CAS  Google Scholar 

  22. Kriaucionis, S. & Heintz, N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929–930 (2009).

    Article  CAS  Google Scholar 

  23. Zoghbi, H.Y. Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302, 826–830 (2003).

    Article  CAS  Google Scholar 

  24. Amir, R.E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG–binding protein 2. Nat. Genet. 23, 185–188 (1999).

    Article  CAS  Google Scholar 

  25. Chahrour, M. & Zoghbi, H.Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007).

    Article  CAS  Google Scholar 

  26. Chen, R.Z., Akbarian, S., Tudor, M. & Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat. Genet. 27, 327–331 (2001).

    Article  CAS  Google Scholar 

  27. Guy, J., Hendrich, B., Holmes, M., Martin, J.E. & Bird, A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 27, 322–326 (2001).

    Article  CAS  Google Scholar 

  28. Hutnick, L.K. et al. DNA hypomethylation restricted to the murine forebrain induces cortical degeneration and impairs postnatal neuronal maturation. Hum. Mol. Genet. 18, 2875–2888 (2009).

    Article  CAS  Google Scholar 

  29. Wilson, V.L., Smith, R.A., Ma, S. & Cutler, R.G. Genomic 5-methyldeoxycytidine decreases with age. J. Biol. Chem. 262, 9948–9951 (1987).

    CAS  PubMed  Google Scholar 

  30. Pastor, W.A. et al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473, 394–397 (2011).

    Article  CAS  Google Scholar 

  31. Szulwach, K.E. et al. Integrating 5-hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genet. 7, e1002154 (2011).

    Article  CAS  Google Scholar 

  32. Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322 (2009).

    Article  CAS  Google Scholar 

  33. Lengner, C.J. et al. Derivation of pre-X inactivation human embryonic stem cells under physiological oxygen concentrations. Cell 141, 872–883 (2010).

    Article  CAS  Google Scholar 

  34. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).

    Article  Google Scholar 

  35. Kuemerle, B., Zanjani, H., Joyner, A. & Herrup, K. Pattern deformities and cell loss in Engrailed-2 mutant mice suggest two separate patterning events during cerebellar development. J. Neurosci. 17, 7881–7889 (1997).

    Article  CAS  Google Scholar 

  36. Song, D.L., Chalepakis, G., Gruss, P. & Joyner, A.L. Two Pax-binding sites are required for early embryonic brain expression of an Engrailed-2 transgene. Development 122, 627–635 (1996).

    CAS  PubMed  Google Scholar 

  37. Lister, R. et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68–73 (2011).

    Article  CAS  Google Scholar 

  38. Muotri, A.R. et al. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435, 903–910 (2005).

    Article  CAS  Google Scholar 

  39. Coufal, N.G. et al. L1 retrotransposition in human neural progenitor cells. Nature 460, 1127–1131 (2009).

    Article  CAS  Google Scholar 

  40. Wu, H. et al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473, 389–393 (2011).

    Article  CAS  Google Scholar 

  41. Hellman, A. & Chess, A. Gene body–specific methylation on the active X chromosome. Science 315, 1141–1143 (2007).

    Article  CAS  Google Scholar 

  42. Deininger, P.L., Moran, J.V., Batzer, M.A. & Kazazian, H.H. Jr. Mobile elements and mammalian genome evolution. Curr. Opin. Genet. Dev. 13, 651–658 (2003).

    Article  CAS  Google Scholar 

  43. Feschotte, C. Transposable elements and the evolution of regulatory networks. Nat. Rev. Genet. 9, 397–405 (2008).

    Article  CAS  Google Scholar 

  44. Zhou, Z. et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth and spine maturation. Neuron 52, 255–269 (2006).

    Article  CAS  Google Scholar 

  45. Nelson, E.D., Kavalali, E.T. & Monteggia, L.M. Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation. J. Neurosci. 28, 395–406 (2008).

    Article  CAS  Google Scholar 

  46. McGraw, C.M., Samaco, R.C. & Zoghbi, H.Y. Adult neural function requires MeCP2. Science 333, 186 (2011).

    Article  CAS  Google Scholar 

  47. Collins, A.L. et al. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum. Mol. Genet. 13, 2679–2689 (2004).

    Article  CAS  Google Scholar 

  48. Szulwach, K.E. et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J. Cell Biol. 189, 127–141 (2010).

    Article  CAS  Google Scholar 

  49. Emig, D. et al. AltAnalyze and DomainGraph: analyzing and visualizing exon expression data. Nucleic Acids Res. 38, W755–762 (2010).

    Article  CAS  Google Scholar 

  50. Huang, D.W., Sherman, B.T. & Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).

    Article  CAS  Google Scholar 

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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.

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Author notes

  1. Keith E Szulwach and Xuekun Li: These authors contributed equally to this work.

Authors and 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.

Corresponding author

Correspondence to Peng Jin.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12 and Supplementary Tables 1 and 2 (PDF 4804 kb)

Supplementary Data Set 1

P7 and 6 week Cerebellum gene expression data (XLSX 5768 kb)

Supplementary Data Set 2

P7 Cerebellum DhMRs (XLSX 6402 kb)

Supplementary Data Set 3

6 week Cerebellum DhMRs (XLSX 5842 kb)

Supplementary Data Set 4

1 year Cerebellum DhMRs (XLSX 3205 kb)

Supplementary Data Set 5

P7 Hippocampus DhMRs (XLSX 2589 kb)

Supplementary Data Set 6

6 week Hippocampus DhMRs (XLSX 3105 kb)

Supplementary Data Set 7

1 year Hippocampus DhMRs (XLSX 1525 kb)

Supplementary Data Set 8

Tissue specific, Stable, and Dynamic DhMRs (XLSX 941 kb)

Supplementary Data Set 9

GO Analyses (XLSX 1868 kb)

Supplementary Data Set 10

Human 5-hmC enriched regions (XLSX 237 kb)

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Szulwach, K., Li, X., Li, Y. et al. 5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat Neurosci 14, 1607–1616 (2011). https://doi.org/10.1038/nn.2959

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