Researchers have explored how methylation patterns have a protein-independent regulatory role that increases the stiffness of DNA, which ultimately impacts the 3D structure of the genome.
DNA methylation is an important epigenetic mark that introduces major changes in cellular functionality. Some of these changes have a systemic impact and can be associated with important pathologies. For example, mutations in DNA Methyltransferase 3a (DNMT3a) are linked with acute myeloid leukaemia. DNA methylation has an important role in development and cell differentiation. In addition, specific methylation levels are critical for the regulation of parental imprinting and X chromosome inactivation. Changes in DNA methylation patterns have also been associated with many different cancers.
While DNA methylation in the promoter region is considered a hallmark of repression, several studies have shown that DNA methylation in the gene body can also affect gene expression. Moreover, studies have shown that an increase in methylation within promoter regions does not necessarily always correlate with gene repression. This highlights that the effects of DNA methylation on gene expression are far more complicated than simply switching it on and off.
Impact of DNA methylation on genome structure
In a recent study, published in Nature Communications, researchers used budding yeast as a model system to determine the intrinsic impact of DNA methylation on genome organisation. This model lacks DNA methylation machinery, making it a perfect model to study the underlying role of DNA methylation in chromatin structure and function.
The team expressed murine DNMT1, DNMT3L, DNMT3a and DNMT3b simultaneously in Saccharomyces cerevisiae cells. Here, they achieved higher methylation rates than previous studies, enabling them to study the impact of methylation. In the absence of any machinery, methylation occurred in a reproducible pattern reminiscent of that seen in mammals. More specifically, methylation was concentrated at linkers and depleted at nucleosomes. Hi-C experiments also revealed significant changes in the global chromatin structure with an increase in gene condensation.
Overall, their results demonstrate that methylation intrinsically modulates chromatin structure and function even in the absence of specific methylation-recognition machinery. This suggests that methylation imprinting has an intrinsic impact on chromatin structure and function.
Image credit: By Molekuul – canva