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A Short Introduction to DNA Methylation
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
Transcription may be affected by DNA methylation in several ways (Figure 1.6). First, the binding of transcriptional activators such as Sp1 and Myc may be inhibited directly by the methylated DNA through sterical hindrance, while other transcription factors especially homeodomain transcription factors are attracted by methylated target recognition sequences (24–26). Methylation of CpG sites in a target sequence can thereby lead to change in transcription factor occupancy at the same sequence and activation of tissue-specific genes (27). Second, methylated DNA is bound by specific methyl-CpG binding domain (MBD1, MBD2, and MBD4) proteins or methyl-CpG binding proteins (MeCP2) as well as proteins of the Kaiso family (12,28,29). They recruit transcriptional co-repressors such as histone deacetylating complexes, polycomb proteins and chromatin remodeling complexes, thereby establishing a repressive closed chromatin configuration (Figure 1.6). Mbd3 binds specifically hydroxymethylated cytosines.
Hibernation and Aging
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Cheng-Wei Wu, Kenneth B. Storey
Active mRNA transcriptional machinery in mammalian cells can account for 1%–10% of its basal metabolic rate, an energetic cost that is not available during hibernation (Rolfe and Brown 1997). In hibernating ground squirrels, the rate of RNA synthesis is reduced at both the initiation and the elongation stage, resulting in a state of transcriptional arrest during torpor (van Breukelen and Martin 2002). The rate of RNA transcription can also be influenced by the accessibility of the DNA template, which are complexed within histone proteins that are subject to posttranslational modifications that determine whether the chromatin is in a transcriptionally active or repressive state (Zhang and Reinberg 2001). The histone tails can undergo a variety of modifications that include acetylation, phosphorylation, methylation, ubiquitination, and more recently known SUMOylation and ADP-ribosylation (Bannister and Kouzarides 2011). When histone acetyltransferase (HAT) proteins acetylate histone tails, chromatins generally exhibit a relaxed and open state and transcription is activated by the increase in accessibility of DNA to interacting proteins. Conversely, when histone tails are deacetylated by histone deacetylase (HDAC) proteins, transcription is suppressed by the formation of the highly repressive heterochromatin structures (Eberharter and Becker 2002). In the skeletal muscle of hibernating ground squirrels, the acetylation of histone H3 was found to be significantly reduced by 25% compared to euthermic squirrels, and this is also accompanied by a 1.8-fold increase in HDAC activity and 1.2–1.5 fold increase in levels of HDAC 1 and 4 proteins (Morin and Storey 2006). Furthermore, activity of RNA polymerase II was also found to be significantly reduced by 43% during hibernation (Morin and Storey 2006). In addition to histone modifications, gene expression can also be controlled via DNA methylation. In general, methylation of DNA is associated with the blocking of gene expression, via changes to the interaction between the DNA and interacting proteins. When methylation takes place at the CpG islands of the promoter, it recruits the binding of methyl-CpG-binding domain proteins (MBDs) that function to block transcription. In the brown adipose tissue, the HDAC proteins are also shown to be upregulated during hibernation, in addition, the global levels of methylated DNA were increased by 1.7-fold, and this increase was coupled with the upregulation of MBD1 protein by 1.9-fold (Biggar and Storey 2014). These results suggest the potential suppression of transcription via increased binding of MBD1 proteins to methylated DNA. Although global transcription effectively ceases during hibernation (van Breukelen and Martin 2002, Morin and Storey 2006), several transcriptomic studies have shown that a cohort of transcripts are actually upregulated during torpor. Genes that are upregulated during hibernation include those involved in stress responses, metabolic regulations, lipid metabolism, and vesicle transports, implicating the importance of these cellular processes in establishing the hibernation phenotype (Hampton et al. 2011, Williams et al. 2011, Schwartz, Hampton, and Andrews 2013).
DNA methylation in pulmonary fibrosis and lung cancer
Published in Expert Review of Respiratory Medicine, 2022
Juan Duan, Baiyun Zhong, Zhihua Fan, Hao Zhang, Mengmeng Xu, Xiangyu Zhang, Yan Y Sanders
Methylated CpG sites are usually recognized by MBPs; at least four (MeCP2, MBD1, MBD2, and MBD4) have been reported in mammals [30]. Some studies have demonstrated that MBPs, such as MeCP2, MBD1, and MBD2, can be recruited to different sites to bind methylated CpG islands [31,32]. For example, MeCP2 and MBD1/2 bind differently to methylated CpG islands in the E-cadherin promoter region [33]. MeCP2 acts as an oncogene in tumorigenesis by silencing genes through hypermethylation in many cancers, including lung cancer [34]. In squamous lung carcinoma tissues, MeCP2 interacts directly with DNMT1 and binds to hypermethylated promoters of tumor suppressor genes such as FHIT, p16INK4a, and RARβ, resulting in lung tumorigenesis and poor prognosis [35,36].
DNA methylation abnormalities in atherosclerosis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Samira Tabaei, Seyyedeh Samaneh Tabaee
DNA methylation through modulating the interaction between DNA and proteins regulates gene transcription. DNA hypermethylation usually leads to a long-term and stable gene suppression until DNA hypomethylation of the gene leads to gene expression. DNA methylation modulates gene expression through two different approaches. The first described way is that the methylated CpG sites impede the attachment of transcription factors to the DNA. The next way is that a family of methyl-CpG binding domain (MBD) proteins, Kaiso (nonhomologous protein) and four homologous proteins (MeCP2, MBD1, MBD2, and MBD4), can bind to the methylated CpG sites.
Emerging DNA methylation inhibitors for cancer therapy: challenges and prospects
Published in Expert Review of Precision Medicine and Drug Development, 2019
Aurora Gonzalez-Fierro, Alfonso Dueñas-González
Abnormal DNA methylation signals may contribute to disease, and the reversible nature of epigenetic alterations makes the DNA methylation machinery an exciting therapeutic target including DNMTs, tet proteins as well as activation-induced cytidine deaminase (AID) protein [34]. In addition, methyl-CpG-binding domain (MBD) proteins which ‘read’ and interpret the methylation moieties on DNA, and are critical mediators of many epigenetic processes, may also targetable. These include at least MBD1, MBD2, MBD3, MBD4, and MeCP2 [35].