Nucleic Acids Research Advance Access originally published online on March 13, 2007
Nucleic Acids Research 2007 35(7):2191-2198; doi:10.1093/nar/gkm118
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Nucleic Acids Research, 2007, Vol. 35, No. 7 2191-2198
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Nucleic Acid Enzymes |
Epigenetic disruption of ribosomal RNA genes and nucleolar architecture in DNA methyltransferase 1 (Dnmt1) deficient cells
1Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), 28029 Madrid, Spain, 2Division of Molecular Biology of the Cell II, German Cancer Research Center, Heidelberg, Germany, 3Adolf Butenandt Institute, Department of Molecular Biology, Ludwig-Maximilians University, D-8036 Munchen, Germany, 4Department of Biochemistry and Molecular Biology, University of Valencia, E-46100 Burjassot, Valencia, Spain, 5Department of Biology, Faculty of Sciences, Autonomous University of Madrid, 28049 Madrid, Spain and 6MRC Human Genetics Unit, Western General Hospital, EH4 2XU Edinburgh, UK
*To whom correspondence should be addressed. Tel: +34-912246940; Fax: +34-91-22856041; Email: mesteller{at}cnio.es
Received November 22, 2006. Revised February 8, 2007. Accepted February 9, 2007.
The nucleolus is the site of ribosome synthesis in the nucleus, whose integrity is essential. Epigenetic mechanisms are thought to regulate the activity of the ribosomal RNA (rRNA) gene copies, which are part of the nucleolus. Here we show that human cells lacking DNA methyltransferase 1 (Dnmt1), but not Dnmt33b, have a loss of DNA methylation and an increase in the acetylation level of lysine 16 histone H4 at the rRNA genes. Interestingly, we observed that SirT1, a NAD+-dependent histone deacetylase with a preference for lysine 16 H4, interacts with Dnmt1; and SirT1 recruitment to the rRNA genes is abrogated in Dnmt1 knockout cells. The DNA methylation and chromatin changes at ribosomal DNA observed are associated with a structurally disorganized nucleolus, which is fragmented into small nuclear masses. Prominent nucleolar proteins, such as Fibrillarin and Ki-67, and the rRNA genes are scattered throughout the nucleus in Dnmt1 deficient cells. These findings suggest a role for Dnmt1 as an epigenetic caretaker for the maintenance of nucleolar structure.
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