Recurrent somatic mutations affecting genes involved in epigenetic regulation of transcription in patients with MDS. Shown are mutations in proteins and complexes affecting (1) histone posttranslational modifications (PTMs); (2) DNA cytosine methylation, hydroxymethylation and demethylation; and (3) mRNA splicing. Copy-number loss and loss-of-function mutations affecting the PRC2 members EZH2, EED, and SUZ12 have been identified recurrently in patients with MDS, and mutations in EZH2 appear to be important predictors of worsened OS in patients with de novo MDS. The PRC2 complex serves to place 1-3 methyl groups on the 27th lysine residue of histone H3 (H3K27). Mutations in ASXL1 are among the most common mutations in patients with MDS, and these mutations have been shown recently to be loss-of-function mutations also associated with loss of H3K27me3. In addition to histone PTMs, mutations affecting DNA cytosine modifications have also been identified in MDS patients, including mutations of unclear function in the de novo DNA cytosine methyltransferase DNMT3A and loss-of-function mutations in the hydroxymethyltransferase TET2. Although the function of hydroxymethylcytosine is not yet totally clear, it is thought to represent an intermediate step in the demethylation of DNA. More recently, mutations in multiple genes encoding members of the spliceosome have also been identified in patients with MDS, including mutations of unclear function in SF3B1, U2AF1, SRFS2, and ZRSR2.