DNA methylation: Superior or subordinate in the epigenetic hierarchy?

Epigenetic modifications are heritable changes in gene expression not encoded by the DNA sequence. In the past decade, great strides have been made in characterizing epigenetic changes during normal development and in disease states like cancer. However, the epigenetic landscape has grown increasingly complicated, encompassing DNA methylation, the histone code, noncoding RNA, and nucleosome positioning, along with DNA sequence. As a stable repressive mark, DNA methylation, catalyzed by the DNA methyltransferases (DNMTs), is regarded as a key player in epigenetic silencing of transcription. DNA methylation may coordinately regulate the chromatin status via the interaction of DNMTs with other modifications and with components of the machinery mediating those marks. In this review, we will comprehensively examine the current understanding of the connections between DNA methylation and other epigenetic marks and discuss molecular mechanisms of transcriptional repression in development and in carcinogenesis.