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

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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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

Authors and Affiliations

Authors

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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