Journal
EPIGENETICS & CHROMATIN
Volume 8, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13072-015-0034-4
Keywords
X chromosome inactivation; DNA methylation; 5-aza-2 '-dC; Ribonucleotide reductase; Hydroxyurea
Categories
Funding
- NIH [DP2OD001686, P01 GM099134]
- CIRM [RN1-00564, RB3-05080, RB4-06133]
- Jonsson Comprehensive Cancer Center
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA
- National Research Service Award [AG039179, GM115122]
- Iris Cantor-UCLA Women's Health Center Executive Advisory Board
- Mangasar M. Mangasarian Scholarship
- UCLA Philip Whitcome pre-doctoral training fellowship
- UCLA Dissertation Year Fellowship
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Background: DNA methylation is important for the maintenance of the silent state of genes on the inactive X chromosome (Xi). Here, we screened for siRNAs and chemicals that reactivate an Xi-linked reporter in the presence of 5-aza-2'-deoxycytidine (5-aza-2'-dC), an inhibitor of DNA methyltransferase 1, at a concentration that, on its own, is not sufficient for Xi-reactivation. Results: We found that inhibition of ribonucleotide reductase (RNR) induced expression of the reporter. RNR inhibition potentiated the effect of 5-aza-2'-dC by enhancing its DNA incorporation, thereby decreasing DNA methylation levels genome-wide. Since both 5-aza-2'-dC and RNR-inhibitors are used in the treatment of hematological malignancies, we treated myeloid leukemia cell lines with 5-aza-2'-dC and the RNR-inhibitor hydroxyurea, and observed synergistic inhibition of cell growth and a decrease in genome-wide DNA methylation. Conclusions: Taken together, our study identifies a drug combination that enhances DNA demethylation by altering nucleotide metabolism. This demonstrates that Xi-reactivation assays can be used to optimize the epigenetic activity of drug combinations.
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