Epigenetic mechanisms in mammals

Abstract

DNA and histone methylation are linked and subjected to mitotic inheritance in mammals. Yet how methylation is propagated and maintained between successive cell divisions is not fully understood. A series of enzyme families that can add methylation marks to cytosine nucleobases, and lysine and arginine amino acid residues has been discovered. Apart from methyltransferases, there are also histone modification enzymes and accessory proteins, which can facilitate and/or target epigenetic marks. Several lysine and arginine demethylases have been discovered recently, and the presence of an active DNA demethylase is speculated in mammalian cells. A mammalian methyl DNA binding protein MBD2 and de novo DNA methyltransferase DNMT3A and DNMT3B are shown experimentally to possess DNA demethylase activity. Thus, complex mammalian epigenetic mechanisms appear to be dynamic yet reversible along with a well-choreographed set of events that take place during mammalian development.

Figure 1

Other nuclear proteins crucial for epigenetic modifications and gene regulation. (A) A simplified example for the role of chromatin remodeling complexes recruited by transcription factors or specific modifications on chromatin [72]. ATP hydrolysis-driven repositioning of nucleosomes exposes an occluded DNA region to allow access of transcriptionalmachinery. (B) Modified histones serve as recognition sites for effector proteins. The illustration shows that trimethylated H3K9 (hexagons) is recognized by HP1 that recruits SUV39H1 and DNMTsto facilitate further H3K9 methylation, HP1 binding, and DNA methylation on adjacent nucleosomes, resulting in repressive chromatin spreading [75, 76]. (C) A model illustrating two major functions of insulators. Insulators (I) placed between an enhancer (E) and promoter blocks enhancer-promoter communication, thereby preventing inappropriate activation of promoters by distant enhancers (left panel). Insulators can also function as a chromatin barrier that limits heterochromatin spreading and prevents repression of neighboring genes (right panel). Condensed heterochromatin is decorated with repressive marks such as H3K9 methylation (hexagons) and DNA methylation (circles).