Although there is no uniform definition of epigenetics, it has been described as heritable changes in gene function that occur without a change in the nucleotide sequence (6
). Epigenetic modifications can be passed from one cell generation to the next (mitotic inheritance) and between generations of a species (meiotic inheritance). In plants, it is well established that epigenetic modifications can be inherited from one generation to the next (7
). However, there is only limited information about the inheritance of epigenetic traits between generations in animals (8
). Notably, epigenetic effects may also be affected by the environment, making them potentially important pathogenic mechanisms in complex multifactorial diseases such as type 2 diabetes (). Epigenetic factors include DNA methylations, histone modifications, and microRNAs, and they can help to explain how cells with identical DNA can differentiate into different cell types with different phenotypes. This perspective will focus on the roles of DNA methylation and histone modification in the pathogenesis of type 2 diabetes.
Model proposing a role for epigenetic mechanisms in the pathogenesis of type 2 diabetes.
Cytosine residues occurring in CG dinucleotides are targets for DNA methylation in vertebrates, and DNA methylation is associated with transcriptional silencing (e.g., on the inactive X chromosome). This silencing can be achieved by either repressing the binding of transcription factors (A
) or by recruiting proteins that specifically bind to methylated CGs (methyl-CG–binding proteins, e.g., MeCP2), which can further recruit histone deacetyltransferases (HDACs) and corepressors (B
FIG. 2. Effects of DNA methylation on gene expression. A: Whereas low levels of DNA methylation at gene promoters have been proposed to generate active genes through increased binding of transcription factors, elevated DNA methylation at promoters may inhibit (more ...)
DNA methylation requires the activity of methyltransferases. There are two groups of DNA methyltransferases: DNMT1, which copies the DNA methylation pattern between cell generations during replication (maintenance methylation), and DNMT3a and DNMT3b, which are responsible for de novo methylation of DNA (10
). The process leading to demethylation of DNA is still poorly understood; for a recent review see Patra et al. (11
Genomic DNA in eukaryotic cells is packed together with special proteins, termed histones, to form chromatin. The basic building block of chromatin is the nucleosome, which consists of ~147 base pairs of DNA wrapped around an octamer of histone proteins that is composed of an H3-H4 tetramer flanked on either side with an H2A-H2B dimer. Although the core histones are densely packed, their NH2
-terminal tails can be modified by histone- modifying enzymes, resulting in acetylation, methylation, phosphorylation, sumoylation, or ubiquitination (12
). These modifications are important for determining the accessibility of the DNA to the transcription machinery as well as for replication, recombination, and chromosomal organization.
HDACs remove and histone acetyl transferases (HATs) add acetyl groups to lysine residues on histone tails (12
). Although, it is well established that HAT activity and increased histone acetylation correlate with increased gene transcription, the exact mechanisms promoting transcription are less clear (15
). Native lysine residues on histone tails contain a positive charge that can bind negatively charged DNA to form a condensed structure with low transcriptional activity. An early suggestion was that histone acetylation removes these positive charges, thereby relaxing chromatin structure and facilitating access to the DNA for the transcriptional machinery to initiate transcription (13
). However, different models have recently been proposed, including the histone code hypothesis, where multiple histone modifications act in combination to regulate transcription (15
). Histone acetylation may also recruit bromodomain proteins that can act as transcriptional activators (13
). Histone methylation can result in either transcriptional activation or inactivation, depending on the degree of methylation and the specific lysine and/or arginine residues modified (17
). Histone methyltransferases and histone demethylases mediate these processes (18
New techniques have made it easier to analyze DNA methylation and histone modifications on a genome-wide scale (19
). These techniques may be useful when studying the impact of epigenetics on the pathogenesis of type 2 diabetes.