DNA Methyltransferase Inhibitor Therapy in the Treatment of Myelodysplastic Syndromes
In the past decade, the science of epigenetics has seen explosive growth. Epigenetics refer to heritable changes in transcription patterns which are not due to structural defects in DNA such as mutations and deletions. An increasing number of important epigenetic alterations have been identified in human cells. The best characterized include the methylation of cytosine residues in CpG dinucleotide sequences. Methylation of such cytosines in CpG-rich regions of gene promoters, referred to as CpG islands, predicts for transcriptional silencing of the gene. Changes in chromatin conformation effect the transcriptional silencing; chromatin conformation depends importantly on post-translational modifications of lysine residues in histone proteins (Fig. 1). The acetylation status of the lysine residues derives from local action of histone acetyltransferases and histone deacetylases (HDACs). Methylated promoters recruit HDACs as the part of transcriptional inhibitory complexes targeted by specific methyl-binding proteins. A wide variety of other epigenetic modifications contribute to this highly complex system, including histone lysine methylation, phosphorylation, ubiquitination, and sumoylation [reviewed in (1,2)].