Cancer is a process driven by the accumulation of abnormalities in gene fun
ction. While many of these changes are genetic, epigenetically mediated cha
nges in gene expression are being increasingly appreciated. This latter pro
cess emphasizes the need to understand two key components of heritable, but
reversible, modulation of gene promoter function that are closely tied to
one another - formation of chromatin which modulates transcription and esta
blishing patterns of DNA methylation, The link lies first in the recruitmen
t to methylated cytosines of a family of methyl-CpG binding domain proteins
(MBDs), which are direct transcriptional repressors and can complex with t
ranscriptional core-pressors including histone deacetylases (HDACs), Additi
onally, the proteins that catalyze DNA methylation, DNA methyltransferases
(DNMTs), also directly repress transcription and associate with HDACs. Regu
lation of these above chromatin-DNA methylation interactions as a function
of DNA replication timing is emerging as a key event in the inheritance of
transcriptionally repressed domains of the genome. Importantly, synergy bet
ween HDAC activity and DNA methylation is operative for a key epigenetic ab
normality in cancer cells, transcriptional silencing of tumor suppressor ge
nes. This change has now been recognized for genes that are essential for n
ormal regulation of virtually every major cell function including cell grow
th, differentiation, apoptosis, DNA repair, and cell-cell, cell-substratum
interaction. Understanding the molecular determinants of both normal and ab
normal patterns of chromatin formation and DNA methylation thus holds great
promise for our understanding of cancer and for means to better diagnose,
prevent, and treat this means to better disease.