![]() ![]() DNMTs utilize methyl groups from SAM, which is a universal methyl donor and acts as a co-factor in this reaction. DNMT3A and DNMT3B add methyl groups to DNA without template DNA and hence, undertake de novo methylation, whereas DNMT1, maintenance DNMT, adds methyl groups to hemi-methylated DNA by copying DNA methylation patterns from the parental strand to the daughter strand during cell division. In mammals, the addition of methyl groups to DNA is carried out by “writers”, DNA methyltransferase (DNMT) 1, DNMT3A, and DNMT3B, converting unmodified C into 5-methyl-cytosine (5mC). However, varying levels of DNA methylation at other regions, including gene bodies, enhancers, 5’ and 3’ UTRs, and partially methylated domains (PMDs), can also differentially affect gene expression to regulate dynamic biological processes. Increased methylation at CpG islands is typically associated with gene silencing. In contrast, there are specific regions where CpG dinucleotides are enriched, called CpG islands, which are primarily located near gene promoters. In the human genome, more than 28 million CpG dinucleotides exist, and 60–80% show methylation in any given cell. The methyl donor for this methylation reaction is s-adenosylmethionine (SAM). DNA methylation is the covalent addition of a methyl (-CH3) group at the cytosine (C) base adjacent to 5’ of a guanosine (G). Specific DNA methylation patterns are crucial for parental imprinting, genomic stability, and importantly, regulation of gene expression. DNA Methylation: Writers, Readers, Erasers, and Co-FactorsĭNA methylation is the most well-characterized epigenetic mechanism, and was linked to cancer as early as the 1980s. This state can be reversed with immunotherapy, such as immune checkpoint inhibitors (ICPi).ġ.1. Cancer can evolve and escape the immune system by developing immunosuppressive escape mechanisms (such as high expression of PD-L1) that allow it to progress. However, some immune cells can be pro-tumor, which paradoxically help tumor progression in the tumor microenvironment. The cancer immunosurveillance system comprises the innate and adaptive immune systems that have various components that help to regress or eliminate tumor cells. Although these abnormalities in malignancy promote tumorigenesis, the cancer immunosurveillance system acts as a tumor suppressor working against the formation of pre-malignant and cancer cells. Recently, abnormal RNA methylation patterns, such as m 6A RNA post-transcriptional modifications (epi-transcriptomics), have been shown to result in the initiation and progression of cancer. Similarly, abnormal epigenetics, such as aberrant DNA methylation patterns, histone modifications, and ncRNA expression (e.g., miRNA) levels, also cause tumorigenesis. ![]() Abnormal genetic modifications such as gene mutations, deletions, amplifications, copy-number variations (CNVs), chromosomal abnormalities, or instability and gene fusions can all result in abnormal expression of genes and proteins leading to transformation of a normal cell into a pre-cancer state and/or cancer stage. ![]() Understanding the complex transcriptional regulation modulating differentiation and function of immune cells can help identify and validate therapeutic targets aimed at targeting DNA and RNA methylation to reduce cancer-associated morbidity and mortality.Ī balance between carcinogenesis and cancer immunosurveillance system. This review considers the role of DNA and RNA methylation in myeloid and lymphoid cells in the activation, differentiation, and function that control the innate and adaptive immune responses in cancer and non-cancer contexts. TME shapes the fate of tumors by modulating the dynamic DNA (and RNA) methylation patterns of these immune cells to alter their differentiation into pro-cancer (e.g., regulatory T cells) or anti-cancer (e.g., CD8+ T cells) cell types. Interactions of tumor and immune cells in the tumor microenvironment (TME) are complex. DNA and RNA methylation play a vital role in the transcriptional regulation of various cell types including the differentiation and function of immune cells involved in pro- and anti-cancer immunity. ![]()
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