Abstract
Since the cloning and discovery of DNA methyltransferases (DNMT), there has been a growing interest in DNA methylation, its role as an epigenetic modification, how it is established and removed, along with the implications in development and disease. In recent years, it has become evident that dynamic DNA methylation accompanies the circadian clock and is found at clock genes in Neurospora, mice and cancer cells. The relationship among the circadian clock, cancer and DNA methylation at clock genes suggests a correlative indication that improper DNA methylation may influence clock gene expression, contributing to the etiology of cancer. The molecular mechanism underlying DNA methylation at clock loci is best studied in the filamentous fungi, Neurospora crassa, and recent data indicate a mechanism analogous to the RNA-dependent DNA methylation (RdDM) or RNAi-mediated facultative heterochromatin. Although it is still unclear, DNA methylation at clock genes may function as a terminal modification that serves to prevent the regulated removal of histone modifications. In this capacity, aberrant DNA methylation may serve as a readout of misregulated clock genes and not as the causative agent. This review explores the implications of DNA methylation at clock loci and describes what is currently known regarding the molecular mechanism underlying DNA methylation at circadian clock genes.
Highlights
DNA methylation is implicated in the etiology of numerous diseases, most notably cancer, and a recent PubMed search revealed over 3000 reviews
The focus of this review is on DNA methylation and chromatin in the circadian clock
There must be amplitude modulation, since the natural antisense transcripts (NATs) are lower abundance relative to their sense counterparts. Our findings and those of others indicate that the antisense transcript is involved in DNA methylation and rhythmic facultative heterochromatin formation at frq; both of which are needed for proper phasing [17,87]
Summary
Methylation on the number 5 carbon of cytosine (5mC) in DNA is found at silenced retrotransposons, imprinted loci and the inactive X chromosome in females [1,2,3,4,5]. The role of DNA methylation in cancer remains enigmatic, with hyper-, hypo- or hemi-methylated sequences all potentially contributing to, or being a consequence of, misregulated expression [6,7] This is due in part to the different regulatory mechanisms by which the methyl group is added to cytosine and further complicated by the discovery that the Tet (ten-eleven translocation) family of proteins can convert 5mC to 5-hydroxymethylcytosine (5hmC) [8]. DNA methylation only appears to be essential for viability in higher vertebrates, providing the counter argument that the complexity of the organism’s genome and the need for carefully controlled and timed differentiation dictates the need for DNA methylation-mediated regulatory function This ongoing debate only serves to pique curiosity and provide continued interest in a modification that appears to be more dynamic than originally thought. DNA methylation, once considered a static permanent modification, is dynamic and may have context-dependent roles
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