All cells in a multicellular organism are genetically identical as they share the same DNA sequence, but have variable gene expression patterns as the result of epigenetic mechanisms. Epigenetic alterations affects all cells, both dividing and non-dividing cells, and tissues throughout life (Talens et al., 2012). The essence of epigenetics is the maintenance of not only the biological function and fate of all cells and tissues, but also their response to environmental influences (Rando and Chang, 2012).
Connecting the genotype with the phenotype, epigenetics is a reversible heritable mechanism that changes either spontaneously or driven by external or internal influences, but without altering the underlying DNA sequence (O’Sullivan and Karlseder, 2012; Zane et al., 2014). Epigenome composes multiple types of epigenetic information, including histones on DNA sequence, DNA methylation, chromatin remodeling, variable structural and functional in histones, posttranslational modifications of the histone proteins, and transcription of noncoding RNAs (ncRNAs) (Brunet and Berger, 2014; Feser and Tyler, 2011).
Chromatin, which carries much of the epigenetic information, is the polymer of nucleosomes that consists of 147 bp DNA wrapping around core histone proteins, H2A, H2B, H3, and H4 (Luger et al., 1997). Epigenetic mechanisms are primarily regulated by a series of enzymes that modify DNA directly or the core histones (methyltransferases, demethylases, acetyltransferases, deacetylases) to regulate gene expression (Rando and Chang, 2009). Epigenetic regulation proceeds by direct methylation and demethylation of DNA bases referring to “Cis-epigenetics” (Bonasio et al.
, 2010). Histones can be altered by modifications of methylation and acetylation which are closely associated with the expression e.g., histone 3 trimethylated at lysine 4 (H3K4me3) and repression of genes e.g.
, histone 3 trimethylated at lysine 27 (H3K27me3) (Wang et al., 2008). Particular modifications on DNA and histones can result in alteration or ease of chromatin states. Growing evidence from aging research show progressive loss in epigenome configuration results in changes in the chromosomal architecture, genomic integrity, and gene expression patterns during aging and in age-related disorders (O’Sullivan and Karlseder, 2012; Brunet and Berger, 2014; Pal and Tyler, 2016). DNA methylation plays a crucial role during development and functions to silence genes no longer needed. Global alterations in DNA methylation patterns at specific sites have been observed during aging.
In young cells, the majority of CpGs are methylated leading to transcriptional repression while the rest of CpGs referring to CpG islands are demethylated resulting in upregulated gene expression (Jung and Pfeifer, 2015). During aging, CpG hypomethylation occurs and increases the risk of genomic instability (Bormann et al., 2016; Zampieri et al., 2015). In addition, the progressive decline in the levels of the DNA methyltransferase (DNMT1) also contributes to the decreased DNA methylation during aging (Jung and Pfeifer, 2015). A study using a DNMT1+/? mouse model showed DNA methylation contributes to age-dependent impaired learning and memory function (Liu et al.
, 2011b). The contribution of DNA methylation to aging is further demonstrated in a recent study of aged pancreatic b cells showing loss of DNA methylation and decreased activity of DNMT1 resulting in aberrant gene expression (Avrahami et al., 2015). Among the histone modifications known to associate with aging and affect longevity, the most conspicuous ones are acetylation and methylation of lysine residues. Studies have demonstrated the age-associated histone modications including increased levels of histone H4K16 acetylation (H4K16Ac), H4K20 trimethylation (H4K20me3), or H3K4 trimethylation (H3K4me3), and decreased levels of H3K9 methylation (H3K9me3) or H3K27 trimethylation (H3K27me3) (Fraga and Esteller, 2007; Han and Brunet, 2012).
DNA methylation and histone modifications function interdependently and both exert changes during aging. During development in both mice and human, the repression of polycomb group protein (PcG)-mediated target genes in specific DNA hypermethylated loci is regulated by H3K27me3 and reversed by H3K4me3. In contrast, during aging, DNA hypermethylation is enriched at the regions carrying bivalent histone marks-both H3K4me3 and H3K27me3 (Weidner and Wagner, 2014; Weidner et al., 2014).
Moreover, DNA hypomethylation couples with the histone marks H3K9Ac, H3K27Ac, H3K4me1~3 found in enhancer regions (Raddatz et al., 2013).