DNA methylation: superior or subordinate in the epigenetic hierarchy?

Abstract

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.

Keywords: DNA methylation; DNA methyltransferase; chromatin; epigenetics; histone code.

Figure 1.

How the histone code may direct DNA methylation during development and carcinogenesis. (A) During normal development, the transcriptionally activating mark H3K4 me3 (x) blocks or repels DNMTs, whereas the repressive marks H3K9me or H3K27me (y) permit or recruit DNMTs, possibly by direct protein-protein interactions (e.g., EZH2-DNMTs). During carcinogenesis, disruption of the histone code in the form of (B) loss of H3K4me3 (x), (C) substitution of H3K4me3 with H3K9me or H3K27me (y), randomization of marks, aberrant acquisition of a new mark (z), or (D) loss of all histone marks permits or actively induces DNMT recruitment. x = H3K4me3; y = H3K9me or H3K27me; z = other histone mark; bent arrow = transcription start site; lollipops = histone marks; black circles = DNA methylation.

Figure 2.

How the histone code may rely on the DNA methylation machinery for direction. Upon binding to CpG-rich regions, DNMTs may directly recruit HMTs to these domains. During DNA replication, UHRF1 preferentially binds hemimethylated DNA and interacts with/recruits DNMT1 and G9A. PCNA may also have a role in the recruitment process. Methyl-CpG–binding proteins (MBDs) specifically interact with methylated DNA and may form complexes with HMTs such as SETDB1 to direct histone methylation to regions of DNA methylation.

Figure 3.

Intragenic CpG islands (CGIs) function as alternative promoters. CGIs embedded in the body of gene T may function as alternative promoters, whose methylation inversely correlates with the transcriptional levels of their corresponding genes. However, the total average level of intragenic DNA methylation appears to display a positive correlation with the transcription of gene T.