Epigenetic mechanisms in mammals

Abstract

Enzymatic modifications of cytosine bases and histone proteins in the nucleosome core provide heritable epigenetic information in vertebrates that is not encoded in the nucleotide sequence of the cell. Chromatin replication during S phase of the cell cycle offers a window of opportunity for these enzymes and accessory factors to load onto the newly synthesized DNA and robustly propagate all the modification marks, as found in the parental cells. Failure to maintain correct epigenetic information leads to catastrophic consequences for the cell, including incorrect gene expression and apoptosis [ 1 – 3 ]. Importantly, cytosine methylation in mammalian cells is faithfully preserved between successive cell divisions. The preservation of DNA methylation during cell division is catalyzed by DNA (cytosine-5) methyltransferases (DNMTs). The major maintenance DNMT enzyme is DNA (cytosine-5) methyltransferase 1 (DNMT1) and has strong preference for hemimethylated DNA in vitro [ 4 ]. Previous studies demonstrate that DNMT1 is stably associated with newly replicated origin in the mammalian cells [ 5 – 7 ]. Therefore, it is plausible that DNMT1 can methylate the newly synthesized daughter strands soon after replication by reading the methylation pattern of the parental strand [ 8 ]. Similarly, there is strong evidence supporting the heritability of histone modifications in multicellular organisms. The strongest evidence links histone H3K27 and H3K4 modification catalyzed by the Polycomb group (PcG) and trithorax group (trxG) to mitotic inheritance of lineage-specific gene expression patterns [ 9 ]. Although some components of trxG and PcG possess histone methyltransferase activities for H3, other components of trxG and PcG interpret those histone marks. These two protein complexes are shown to be critical regulators of numerous developmental genes. They silence or activate a gene via binding to specific regions of a gene and post-translationally modifying the histones. Some recent works have also demonstrated that PcG-mediated gene silencing may involve non-coding RNA and RNAi machinery [ 9 ]. Thus, the model of histone modification inheritance is more complex than DNA methylation due to replication-independent histone deposition on DNA [ 10 ]. Nevertheless, there is strong speculation that a large number of histone modifications may follow epigenetic inheritance mechanisms. Recent advances in sequencing technology, higher computational capacity and highly specific antibodies against histone modifications have resulted in greater understanding of epigenetic marks in the context of mammalian genome. The flurry of research activity has resulted in several very excellent publications [ 11 – 13 ]. In this review, we have attempted to give readers a general overview of the epigenetic mechanisms in mammals by discussing histone and DNA modifications along with the involvement of RNA in both developmental and biological context.