Methylation and epigenetic fidelity

Mammalian cellular differentiation and development depend on stable, somatically heritable epigenetic switches. A good example is X chromosome inactivation, the random silencing of either the paternal or maternal X chromosome but not both. Once silenced, genes on the inactive X (Xi) remain genetically silent in all progeny cells, even though identical genes on the active X (Xa) in the same nucleus are expressed. In most human cells, reactivation of a silent gene on the Xi is below the level of detection (1). Methylation changes are frequent in cancer cells and difficult to distinguish from mutations, leading to the burgeoning field of cancer epigenetics (2, 3). Epigenetics, the study of changes in gene function that do not depend on changes in primary DNA sequence (4), depends on stable, heritable marking of DNA or chromatin. Because heritability is such a key feature, important questions are: What is the fidelity with which an epigenetic state is transmitted from one cell generation to the next? How frequent are mistakes? Are there epigenetic repair mechanisms? This Commentary will discuss three articles relevant to these questions: ( i ) an important study of methylation fidelity by Laird et al. (5) reported in this issue of PNAS, ( ii ) a recent study of de novo methylation by Chen et al. (6), and ( iii ) a kinetic treatment of dynamic, stochastic DNA methylation (7). Cytosine DNA methylation was the first epigenetic mark correctly identified (8, 9) and its inheritance mechanism at least superficially understood (10). 5-Methylcytosine (mC) is found mainly in symmetrical CpG dyads (mCG/GmC), which are transiently converted to hemimethylated sites (mCG/GC) by DNA replication but then converted back to symmetrically methylated sites by a DNA methyltransferase with high specificity for hemimethylated CpG sites. The method of Laird et al. (5) (Fig. 1 …

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