This project contains all information pertaining to the replication of key experiments from this paper. It includes the detailed protocols, including reagents and author clarifications. We also include any comments from other contributors, researchers from the Science Exchange network, and further information with the original authors that we have learned since the beginning of the project. When experimental studies begin all data collected will also be deposited here, including data analysis and eventually the final written report. <br> **Original citation:** Xu W., Yang H., Liu Y., Yang Y., Wang P., Kim S.-H., Ito S., Yang C., Wang P., Xiao M.-T., Liu L.-X., Jiang W.-Q., Liu J., Zhang J.-Y., Wang B., Frye S., Zhang Y., Xu Y.-H., Lei Q.-Y., Guan K.-L., Zhao S.-M., Xiong Y. Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of alpha-Ketoglutarate-Dependent Dioxygenases. Cancer Cell. 2011 Jan 18;19(1):17-30. doi: 10.1016/j.ccr.2010.12.014. <br> **Original paper abstract:** 1DH1 and 1DH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of alpha-ketoglutarate (alpha-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple alpha-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as alpha-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and 1DH2 mutations reduce alpha-KG and accumulate an alpha-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.