Origin of aberrant epigenetic programs in MDS. MDS carries an altered epigenome that results in stable gene expression changes represented by a heatmap on the right side of the figure. These can be influenced by DNA methylation (5mC) and histone code posttranslational modifications such as histone H3 lysine 27 trimethylation (H3K27me3) and acetylation (Ac) of multiple residues on histone H3 and H4. Cytosine hydroxymethylation (5hmC) influences 5mC content and may have direct effects on gene expression (arrow with a question mark). There are also complex correlations between DNA methylation and histone modifications. Molecularly, 5hmC can be altered by TET2 mutations, 5mC is altered by age-related drift and possibly by DNMT3a mutations, and H3K27me3 is potentially influenced by ASXL1 and EZH2 mutations. However, the precise links between TET2 mutations, DNMT3a mutations, and DNA methylation in MDS remain somewhat uncertain (illustrated by dotted lines). Changes in micro-RNA expression (due to genetic or epigenetic lesions) also influence the final gene expression patterns and it is possible (though speculative) that spliceosome mutations also do this. It remains unclear how much of the final MDS gene expression patterns are driven by the described epigenetic alterations, and the heterogeneity of the disease implies that these mechanisms may be more important in some cases than in others.