Fig.1. Western blot analysis of DNA methyltransferase 1 knockout 293T (KO) and wild type (WT) whole cell lysates probed with Rabbit Anti-DNA Methyltransferase 1 Antibody (VPA00026).
Epigenetics investigates heritable changes in gene expression without changes to the DNA sequence. Epigenetic mechanisms, such as DNA methylation, chromatin remodeling, and noncoding RNAs, regulate cell growth, development, and differentiation (Bird 2007).
DNA methylation is the addition of a methyl group to a cytosine nucleotide particularly within the CpG dinucleotide. The methylation of CpG sites is performed by DNA methyltransferases (DNMTs) (Egger et al. 2004). The canonical DNMT enzymes are DNMT1 (Figure 1), DNMT3A, and DNMT3B (Bestor 2000). DNA methylation regulates transcription, chromatin structure, DNA repair, and X chromosome inactivation. It is also important for the developmental control of gene expression (Robertson 2001 and 2002).
Histones are a family of proteins that are found in the nucleus and function to package DNA into nucleosomes. The amino-terminal tail domains of histones can be modified through acetylation and methylation. Histone acetylation usually denotes active chromatin, whereas deacetylation is found in transcriptionally inactive regions. Histone methylation marks both active and inactive regions of chromatin (Egger et al. 2004). Histone modifications also include arginine citrullination and Ser/Thr/Tyr phosphorylation. The majority of histone alterations control DNA transcription (Fardi et al. 2018).
MicroRNAs (miRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), and long noncoding RNAs (lncRNAs) are all epigenetic related noncoding RNAs (Cheng et al. 2019). Noncoding RNAs regulate gene expression and genome stability (Holoch and Moazed 2015).
Tumor cells have different DNA methylation patterns compared to normal cells (Goelz et al. 1985). In cancer cells, hypomethylation in the DNA and hypermethylation at other sites are observed. Hypomethylation can cause expression of oncogenes whereas hypermethylation results in inhibition of tumor suppressor genes (Fardi et al. 2018). CpG islands, regions of the genome with a high number of CpG dinucleotide repeats, are extensively methylated in cancer cells (Robertson 2001 and 2002). Aberrant promoter methylation is linked to a loss of gene function. For example, silencing of BRCA1 by promoter hypermethylation occurs in sporadic variants of breast and ovarian cancer (Esteller et al. 2000). The methylation of EN1 has been found to be elevated in human salivary gland cystic carcinoma (Achim et al. 2011). Methylation levels have been demonstrated to be positively related to tumor size (Christensen et al. 2010).
Inhibition of histone/protein deacetylases (HDAC) has been shown in clinical and experimental investigations to have major anti-neoplastic effects via cytotoxic and proapoptotic pathways (Akimova T et al. 2012). Rett, ATRX, and fragile X syndromes are caused by naturally occurring mutations in genes that affect DNA methylation patterns (Robertson and Wolffe 2000). Epigenetic dysregulation also has a direct impact on the development of autoimmunity (Moosavi et al. 2016). Particularly, DNA methylation plays a significant role in autoimmune disorders by modifying gene expression profiles (Chen et al. 2016; Paul et al. 2016).
Epigenetic changes may potentially predict clinical outcomes. Large-scale genome-wide DNA methylation profiling revealed that specific DNA methylation patterns are characteristic of different forms of acute myeloid leukemia (Figueroa et al. 2010). Histone lysine methylation can be used as a key indicator of prostate cancer recurrence (Ellinger et al. 2010).
Due to the reversible nature of the epigenetic modifications, various epigenetic therapeutic approaches have emerged. The FDA approved the inhibition of DNMTs and HDACs in cancer treatment (Fardi et al. 2018).
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