International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 227-238 http://medscipublisher.com/index.php/ijmms 230 are crucial for regulating gene expression and maintaining genomic stability, and their dysregulation is associated with various cancers (Ichiyama et al., 2015; Shekhawat et al., 2021). 4.3 Biological Functions of DNA Methylation 4.3.1 Gene expression regulation DNA methylation is a key regulator of gene expression. Methylation of promoter regions typically leads to transcriptional repression by preventing the binding of transcription factors and recruiting repressive chromatin modifiers (Baubec et al., 2015). Conversely, demethylation by TET enzymes can activate gene expression by removing repressive methylation marks (Ichiyama et al., 2015; Seiler et al., 2018). This dynamic regulation is essential for cellular differentiation and response to environmental signals (Ichiyama et al., 2015; Liu et al., 2016). 4.3.2 Genomic stability DNA methylation contributes to genomic stability by suppressing the activity of transposable elements and maintaining the integrity of repetitive sequences (Baubec et al., 2015). DNMTs play a critical role in this process by ensuring that these regions remain methylated and transcriptionally silent, thus preventing genomic instability and potential mutagenesis (Baubec et al., 2015). 4.3.3 X-Chromosome inactivation X-chromosome inactivation is a process by which one of the two X chromosomes in female mammals is transcriptionally silenced to achieve dosage compensation. DNA methylation is a key mechanism in this process, ensuring the stable and heritable silencing of the inactive X chromosome (Uysal et al., 2015). DNMTs are involved in establishing and maintaining the methylation patterns necessary for X-chromosome inactivation (Uysal et al., 2015). 4.3.4 Imprinting Genomic imprinting is an epigenetic phenomenon where certain genes are expressed in a parent-of-origin-specific manner. DNA methylation plays a crucial role in imprinting by differentially marking the maternal and paternal alleles, leading to monoallelic expression (Uysal et al., 2015). DNMTs are responsible for establishing these imprinted methylation marks during gametogenesis and early embryonic development (Uysal et al., 2015). DNA methylation is a versatile and dynamic epigenetic modification that plays essential roles in gene regulation, genomic stability, X-chromosome inactivation, and imprinting. The coordinated action of DNMTs and TET enzymes ensures the proper establishment, maintenance, and removal of methylation marks, thereby orchestrating complex biological processes. 5 DNA Methylation in Colon Cancer 5.1 Global DNA methylation changes Global DNA methylation changes are a hallmark of colon cancer, characterized by widespread hypomethylation and focal hypermethylation of CpG islands. Hypomethylation can lead to genomic instability, which is a common feature in cancer cells (Sharma et al., 2010; Pfeifer, 2018). Conversely, hypermethylation of CpG islands, particularly in promoter regions, is associated with the silencing of tumor suppressor genes, contributing to cancer progression (Moarii et al., 2015). These global changes in DNA methylation are not only pivotal in the initiation and progression of colon cancer but also serve as potential biomarkers for diagnosis and prognosis (Jung et al., 2020; Davalos and Esteller, 2022). 5.2 Gene-Specific DNA methylation patterns 5.2.1 Tumor suppressor genes In colon cancer, the hypermethylation of promoter CpG islands in tumor suppressor genes is a well-documented phenomenon. This epigenetic silencing leads to the inactivation of critical genes involved in cell cycle regulation, DNA repair, and apoptosis. For instance, genes such as APC, MLH1, and CDKN2A are frequently hypermethylated in colon cancer, resulting in their transcriptional repression and contributing to tumorigenesis (Jung et al., 2020).
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