Abstract
BackgroundPrevious studies of individual genes have shown that in a self-enforcing way, dimethylation at histone 3 lysine 9 (dimethyl-H3K9) and DNA methylation cooperate to maintain a repressive mode of inactive genes. Less clear is whether this cooperation is generalized in mammalian genomes, such as mouse genome. Here we use epigenomic tools to simultaneously interrogate chromatin modifications and DNA methylation in a mouse leukemia cell line, L1210.ResultsHistone modifications on H3K9 and DNA methylation in L1210 were profiled by both global CpG island array and custom mouse promoter array analysis. We used chromatin immunoprecipitation microarray (ChIP-chip) to examine acetyl-H3K9 and dimethyl-H3K9. We found that the relative level of acetyl-H3K9 at different chromatin positions has a wider range of distribution than that of dimethyl-H3K9. We then used differential methylation hybridization (DMH) and the restriction landmark genome scanning (RLGS) to analyze the DNA methylation status of the same targets investigated by ChIP-chip. The results of epigenomic profiling, which have been independently confirmed for individual loci, show an inverse relationship between DNA methylation and histone acetylation in regulating gene silencing. In contrast to the previous notion, dimethyl-H3K9 seems to be less distinct in specifying silencing for the genes tested.ConclusionThis study demonstrates in L1210 leukemia cells a diverse relationship between histone modifications and DNA methylation in the maintenance of gene silencing. Acetyl-H3K9 shows an inverse relationship between DNA methylation and histone acetylation in regulating gene silencing as expected. However, dimethyl-H3K9 seems to be less distinct in relation to promoter methylation. Meanwhile, a combination of epigenomic tools is of help in understanding the heterogeneity of epigenetic regulation, which may further our vision accumulated from single-gene studies.
Highlights
Previous studies of individual genes have shown that in a self-enforcing way, dimethylation at histone 3 lysine 9 and DNA methylation cooperate to maintain a repressive mode of inactive genes
Current knowledge supports the idea that repressive complexes, containing both methyl binding domain (MBD) proteins and histone deacetylases (HDACs), in combination with other repressor proteins, direct DNA methylation and subsequently transcriptional repression [9]
Using genome-wide data, we demonstrate that histone acetylation and histone methylation show a distinct degree of autonomy with respect to promoter methylation
Summary
Previous studies of individual genes have shown that in a self-enforcing way, dimethylation at histone 3 lysine 9 (dimethyl-H3K9) and DNA methylation cooperate to maintain a repressive mode of inactive genes. Additional evidence shows that DNA methylation impacts histone methylation and that DNA methylation might exert a positive feedback on lysine methylation [10,11,12,13,14]. To reconcile these two seemingly distinct mechanisms, a self-enforcing network of epigenetic regulation has been proposed: histone methylation impacts DNA methylation and histone acetylation which in turn impacts histone methylation [3,9]
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