Gain and loss of DNA methylation in cells is a dynamic process that tends to achieve an equilibrium. Many factors are involved in maintaining the balance between DNA methylation and demethylation. Previously, it was shown that methyl-DNA protein Kaiso may attract NCoR, SMRT repressive complexes affecting histone modifications. On the other hand, the deficiency of Kaiso resulted in reduced methylation of ICR in H19/Igf2 locus and Oct4 promoter in mouse embryonic fibroblasts. However, nothing is known about how Kaiso influences DNA methylation at the genome level. Here we show that deficiency of Kaiso led to whole-genome hypermethylation, using Kaiso deficient human renal cancer cell line obtained via CRISPR/CAS9 genome editing. However, Kaiso serves to protect genic regions, enhancers, and regions with a low level of histone modifications from demethylation. We detected hypomethylation of binding sites for Oct4 and Nanog in Kaiso deficient cells. Kaiso immunoprecipitated with de novo DNA methyltransferases DNMT3a/3b, but not with maintenance methyltransferase DNMT1. Thus, Kaiso may attract methyltransferases to surrounding regions and modulate genome methylation in renal cancer cells apart from being methyl DNA binding protein.

DNA methylation is the most important epigenetic modification involved in the regulation of transcription, imprinting, establishment of X-inactivation, and the formation of a chromatin structure. DNA methylation in the genome is often associated with transcriptional repression and the formation of closed heterochromatin. However, the results of genome-wide studies of the DNA methylation pattern and transcriptional activity of genes have nudged us toward reconsidering this paradigm, since the promoters of many genes remain active despite their methylation. The differences in the DNA methylation distribution in normal and pathological conditions allow us to consider methylation as a diagnostic marker or a therapy target. In this regard, the need to investigate the factors affecting DNA methylation and those involved in its interpretation becomes pressing. Recently, a large number of protein factors have been uncovered, whose ability to bind to DNA depends on their methylation. Many of these proteins act not only as transcriptional activators or repressors, but also affect the level of DNA methylation. These factors are considered potential therapeutic targets for the treatment of diseases resulting from either a change in DNA methylation or a change in the interpretation of its methylation level. In addition to protein factors, a secondary DNA structure can also affect its methylation and can be considered as a therapy target. In this review, the latest research into the DNA methylation landscape in the genome has been summarized to discuss why some DNA regions avoid methylation and what factors can affect its level or interpretation and, therefore, can be considered a therapy target.

Understanding the phenotypic consequences of epigenetic variation and its role in adaptation remains a central challenge in evolutionary biology. Marine and freshwater sticklebacks provide a powerful system to study the interplay between genetic and epigenetic components of phenotypic plasticity that enables colonization of contrasting salinity habitats. Here, we used whole-genome bisulfite sequencing (WGBS) to characterize DNA methylation entropy—a measure of epigenetic stochasticity—in gill tissue from marine and freshwater ecotypes. We found that freshwater sticklebacks exhibit elevated methylation entropy in divergence islands (DIs), genomic regions known as hotspots of genetic divergence between marine and freshwater populations. Within DIs, we identified a subset of genes exhibiting concurrent increases in methylation entropy and transcriptional variance, including osmoregulatory candidates involved in growth modulation, cytoskeletal reorganization, metabolism, and extracellular matrix remodeling. Their linked variability suggests that they may act as “adaptation capacitors” facilitating phenotypic plasticity during salinity transitions. Exploratory enrichment analysis further revealed overrepresented epigenetic regulators within DIs, such as DNA demethylase TET1 and chromatin remodelers ARID5B and BPTF, indicating a potential regulatory basis by which these factors may convert genetic variation into epigenetic diversity. Collectively, our findings demonstrate that DIs are focal points of both genetic divergence and epigenetic heterogeneity, consistent with a model in which DIs may act as multi-layered genomic regions associated with adaptive responses to salinity change.