The Nuclear DNA Base 5-Hydroxymethylcytosine Is Present in Purkinje Neurons and the Brain
Methylation Mediation
Methylation of cytosine bases, 5-methylcytosine (5mC), in DNA plays an important regulatory role in mammalian genomes. Methylation patterns are often inherited across generations, but they can also be dynamic, suggesting that active DNA demethylation pathways exist. One such pathway, best characterized in plants, involves the removal of the 5mC base, and its replacement by C, via a DNA repair mechanism. Kriaucionis and Heintz (p. 929, published online 16 April) now show that, as well as 5mC in mammalian genomes, there are also significant amounts of 5-hydroxymethylcytosine (5hmC) in DNA of Purkinje neurons, which have large nuclei with apparently very little heterochromatin. Tahiliani et al. (p. 930, published online 16 April) find that the protein TET1 is capable of converting 5mC into 5hmC both in vitro and in vivo. 5-Hydroxymethylcytosine is also present in embryonic stem cells, and levels of 5hmC and TET1 show correlated variation during cell differentiation.
Abstract
Despite the importance of epigenetic regulation in neurological disorders, little is known about neuronal chromatin. Cerebellar Purkinje neurons have large and euchromatic nuclei, whereas granule cell nuclei are small and have a more typical heterochromatin distribution. While comparing the abundance of 5-methylcytosine in Purkinje and granule cell nuclei, we detected the presence of an unusual DNA nucleotide. Using thin-layer chromatography, high-pressure liquid chromatography, and mass spectrometry, we identified the nucleotide as 5-hydroxymethyl-2′-deoxycytidine (hmdC). hmdC constitutes 0.6% of total nucleotides in Purkinje cells, 0.2% in granule cells, and is not present in cancer cell lines. hmdC is a constituent of nuclear DNA that is highly abundant in the brain, suggesting a role in epigenetic control of neuronal function.
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Science
Volume 324 | Issue 5929
15 May 2009
15 May 2009
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Copyright © 2009, American Association for the Advancement of Science.
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Received: 15 December 2008
Accepted: 18 March 2009
Published in print: 15 May 2009
Acknowledgments
We thank B. Gauthier for technical assistance; S. Mazel, C. Bare, and X. Fan for flow cytometry advice and nuclei sorts; and H. Deng and J. Fernandez for acquirement of MS data and help with HPLC. We are grateful to members of the Heintz laboratory for discussions and support. This work was supported by the Howard Hughes Medical Institute and the Simons Foundation Autism Research Initiative.
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- Skirmantas Kriaucionis,
- Nathaniel Heintz
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