Genetic alterations of epigenetic pathways in MDS. The normal function of selected factors important for histone modification and DNA methylation is depicted. Left panel: In most cases, the biological consequences of mutations in these pathways is not yet well-established. Trimethylation (me3) of lysine 27 (K27) on the carboxyterminal tail of histone H3, a nucleosome component, is associated with transcriptional repression. ASXL1 is a polycomb repressive complex protein that maintains the repressive state. Both ASXL1 and EZH2 (encoding an H3K27 methyltransferase) are frequently mutated in MDS. Rare mutations (deletions) have also been identified in MDS samples in H3K27 demethylase enzymes, including UTX and other JmjC domain–containing proteins. Right panel: Cytosine methylation in CpG islands is associated with transcriptional repression. DNMT3A is a de novo DNA methyltransferase that converts unmethylated cytosine to 5mC. 5mC is converted to 5hmC by the TET proteins in the presence of αKG generated by the IDH enzymes. DNMT3A, TET2, IDH1, and IDH2 are all recurrently mutated in MDS samples.