The role of DNA methylation in the pathogenesis of type 2 ... ... Diabetes mellitus Diabetes...
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REVIEW Open Access
The role of DNA methylation in the pathogenesis of type 2 diabetes mellitus Sanabil Ali Hassan Ahmed1, Suraiya Anjum Ansari2, Eric P. K. Mensah-Brown1 and Bright Starling Emerald1*
Diabetes mellitus (DM) is a chronic condition characterised by β cell dysfunction and persistent hyperglycaemia. The disorder can be due to the absence of adequate pancreatic insulin production or a weak cellular response to insulin signalling. Among the three types of DM, namely, type 1 DM (T1DM), type 2 DM (T2DM), and gestational DM (GDM); T2DM accounts for almost 90% of diabetes cases worldwide. Epigenetic traits are stably heritable phenotypes that result from certain changes that affect gene function without altering the gene sequence. While epigenetic traits are considered reversible modifications, they can be inherited mitotically and meiotically. In addition, epigenetic traits can randomly arise in response to environmental factors or certain genetic mutations or lesions, such as those affecting the enzymes that catalyse the epigenetic modification. In this review, we focus on the role of DNA methylation, a type of epigenetic modification, in the pathogenesis of T2DM.
Keywords: Diabetes mellitus, DNA methylation, Type 2 diabetes mellitus, Hypermethylation, Hypomethylation
Introduction Diabetes mellitus Diabetes mellitus (DM) is a chronic condition charac- terised by persistently elevated glucose levels in the bloodstream (i.e., hyperglycaemia)  and pancreatic β cell dysfunction . In general, the disease is classified into three types, namely, type 1 DM (T1DM), type 2 DM (T2DM), and gestational DM (GDM), with T2DM accounting for approximately 90% of diabetes cases worldwide. In T2DM, the associated hyperglycaemia can be due to inadequate pancreatic insulin production or a weak cellular response to insulin signalling (i.e., insulin resistance). In addition, the development of T2DM de- pends, in part, on the balance between pancreatic β cell proliferation and apoptosis [1, 3]. T2DM is a multifactorial disease, with its aetiology
affected by multiple genes (i.e., polygenic) in addition to
environmental factors. Indeed, genome-wide association studies (GWASs) have linked aberrations in more than 40 different genes with an increased risk of T2DM. These genes are involved in the regulation of various biological processes, including cellular development, differentiation, and physiological functions. Environmen- tal factors that have been associated with an increased risk of T2DM include age, obesity, and lack of physical activity . The persistent hyperglycaemia in DM can ultimately
lead to adverse complications, such as neuropathy, ret- inopathy, nephropathy, and cardiovascular diseases (CVDs). As a compounding factor, there is a prolonged pre-detection period in T2DM, during which one third to one half of all patients may go undiagnosed due to a lack of clinical symptoms. Indeed, some patients are only diagnosed with T2DM after the manifestation of complications associated with T2DM-induced hypergly- caemia [1, 3]. The latest statistics of the prevalence of DM (as of
2019) and the predicted statistics of the prevalence of
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* Correspondence: firstname.lastname@example.org 1Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al Ain, Abu Dhabi, United Arab Emirates Full list of author information is available at the end of the article
Ahmed et al. Clinical Epigenetics (2020) 12:104 https://doi.org/10.1186/s13148-020-00896-4
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DM for the years 2030 and 2045 are summarised in Fig. 1 . Despite the high prevalence of DM, the exact mechanisms underlying the development of GDM, T1DM, and T2DM are not fully understood [1, 3]. Therefore, a greater understanding of the aetiology of DM is necessary to develop improved prevention and diagnostic tools and treatments for associated complications.
Epigenetics An epigenetic trait is a stably heritable phenotype resulting from certain changes in gene expression that do not alter the underlying DNA sequence . Epigenetic traits are con- sidered reversible modifications that can be inherited mitot- ically and meiotically. However, they can also randomly
arise due to various environmental factors or genetic muta- tions such as those affecting the enzymes that catalyse the epigenetic modification [5, 6]. Important epigenetic modifi- cations include DNA methylation; posttranslational histone tail modifications, such as methylation, phosphorylation, acetylation, and regulatory RNAs . In general, epigenetic modifications do not occur
independently but rather crosstalk with and regulate one another to create an epigenetic profile, which changes the function of the genome (gene expression) by altering the chromatin structure. The particular epigenetic profile can either lead to gene activation by relaxing the chromatin structure, thus allowing the transcription machinery to access the DNA, or to gene silencing by tightly packaging the chromatin structure and inhibiting
Fig. 1 Worldwide DM statistics in 2019 for the age group 20–79 years old and the projections for years 2030 and 2045
Ahmed et al. Clinical Epigenetics (2020) 12:104 Page 2 of 23
access to the DNA . Accordingly, the epigenetic profile has been shown to modulate gene expression in different cell types, developmental stages, and in health and disease states . Three categories of signals that stimulate an epigenetic
state have been proposed, namely, epigenators, epigen- etic initiators, and epigenetic maintainers (Fig. 2). The epigenator signal is environmentally induced and trig- gers an intracellular pathway. It can be a modification- based event or a protein–protein interaction that releases the dormant activity of the epigenetic initiator. An example of an epigenator signal is temperature (in plants). The extracellular epigenator signal is received and transmitted by the intracellular epigenetic initiator signal, which translates the signal by initiating events re- quired for establishing the signalled chromatin state at the chromatin location. The initiator signal can be non- coding RNAs, DNA-binding proteins and/or any entity capable of recognising DNA sequences and defining the chromatin state to be generated. An epigenetic main- tainer signal maintains the chromatin state over subse- quent generations, although not sufficiently enough to initiate it. This signal maintainer preserves the epigenetic profile in terminally differentiated cells and throughout the cell cycle. Examples include the DNA methylation of CpG islands .
DNA methylation DNA methylation, which naturally occurs as a result of DNA replication, is the covalent addition of a methyl group (–CH3) to the 5’ position of the cytosine residue in the dinucleotide 5’-cytosine-phosphodiester bond- guanine-3’ (5’-CpG-3’) to form 5-methylcytosine (5mC). CpG DNA methylation is reversible [6, 9]. CpG islands have a high CpG density (> 50%) and are primarily lo- cated in the promoter region of genes but can also be found in enhancer and intragenic regions [5, 6]. Al- though 70% of CpG dinucleotides are methylated in humans, CpG dinucleotides of germ-line cells and pro- moters of somatic cells are relatively unmethylated . In general, promoter CpG island hypomethylation is
associated with transcriptional activation, whereas the hypermethylation of CpG islands is associated with tran- scriptional silencing. However, the methylation of CpG sites in regulatory regions outside the gene promoter also plays a role in regulating gene expression in a tissue-specific manner, thus making gene expression regulation through DNA methylation considerably more complex than simple promoter methylation. The process of gene silencing by DNA methylation is required for critical biological processes, such as cellular differenti- ation, genomic imprinting, X chromosome inactivation, and retrotransposon silencing. To date, two mechanisms
Fig. 2 The epigenetic pathway and the three categories of signals proposed. The extracellular epigenator signal triggers the initiation of the epigenetic pathway. The epigenetic initiator receives the signal from the epigenator and determines the chromatin state for establishing the epigenetic pathway. The epigenetic maintainer sustains the chromatin state in succeeding generations
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