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Clinical Chemistry 54: 1125-1131, 2008. First published May 16, 2008; 10.1373/clinchem.2007.101766
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(Clinical Chemistry. 2008;54:1125-1131.)
© 2008 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Sequence-Specific Histone Methylation Is Detectable on Circulating Nucleosomes in Plasma

Ugur Deligezer1, Ebru E. Akisik1, Nilgün Erten2 and Nejat Dalay1,a

1 Department of Basic Oncology, Oncology Institute, and 2 Department of Internal Medicine, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.

aAddress correspondence to this author at: Istanbul University, Oncology Institute, 34390 Capa, Istanbul, Turkey. E-mail ndalay{at}yahoo.com

Background: Alterations in DNA methylation and histone modifications have been implicated in carcinogenesis. Although tumor-specific alterations in DNA methylation can be detected in the serum and plasma of cancer patients, no data are available on the presence of histone modifications in circulating blood. We investigated whether histone methylation, as a model of histone modifications, is detectable in plasma. Because methylation at histone 3 lysine 9 (H3K9) has been demonstrated to be enriched at sites of repetitive ALU elements, we addressed the specificity of histone-methylation detection and hypothesized that if monomethylated H3K9 (H3K9me1) is detectable in plasma, the concentrations in mononucleosomes and oligonucleosomes would be different. We also analyzed a single-copy gene, CDKN2A.

Methods: We enrolled 21 multiple myeloma patients in the study. We used ELISA and real-time PCR analysis to evaluate nucleosomes and cell-free DNA, respectively, as evidence of the presence of histones and associated DNA in circulating blood. H3K9me1 was analyzed by chromatin immunoprecipitation.

Results: ELISA and real-time PCR assays indicated the presence of free nucleosomes and DNA in plasma, and the results were quantitatively correlated (P < 0.001). The detection of histone methylation on free nucleosomes was sequence dependent. Fragments representing mono- and oligonucleosomes differed with respect to H3K9me1 concentrations (P = 0.004), in accordance with our hypothesis. In addition, the detection rate and concentrations of H3K9me1 were significantly higher on the fragment covering both mononucleosomes and oligonucleosomes than on the CDKN2A promoter (P < 0.001).

Conclusions: If validated in further studies, our findings may be a basis for investigations of cancer-specific alterations in histone modifications in the circulation.




The following articles in journals at HighWire Press have cited this article:


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S. Holdenrieder, F. T. Kolligs, and P. Stieber
New Horizons for Diagnostic Applications of Circulating Nucleosomes in Blood?
Clin. Chem., July 1, 2008; 54(7): 1104 - 1106.
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