Epigenetics and Gene Expression

Heredity (2010) 105, 4–13 & 2010 Macmillan Publishers Limited All rights reserved 0018-067X/10 $32.00 www.nature.com/hdy REVIEW Epigenetics and gene expression ER Gibney1,2 and CM Nolan2,3 1UCD Institute of Food and Health, Dublin, Ireland; 2UCD College of Life Sciences Epigenetic Research Group (CERGU), Dublin, Ireland and 3UCD School of Biology and Environmental Science, Dublin, Ireland Transcription, translation and subsequent protein modification processes, including DNA methylation, histone modification and represent the transfer of genetic information from the archival various RNA-mediated processes, are thought to influence gene copy of DNA to the short-lived messenger RNA, usually with expression chiefly at the level of transcription; however, other subsequent production of protein. Although all cells in an steps in the process (for example, translation) may also be organism contain essentially the same DNA, cell types and regulated epigenetically. The following paper will outline the role functions differ because of qualitative and quantitative differ- epigenetics is believed to have in influencing gene expression. ences in their gene expression. Thus, control of gene expression Heredity (2010) 105, 4–13; doi:10.1038/hdy.2010.54; is at the heart of differentiation and development. Epigenetic published online 12 May 2010 Keywords: epigenetics; gene expression; DNA methylation; histone modification; chromatin remodelling; non-coding RNA Epigenetics and gene expression Gene expression is a complex process involving numerous steps (Alberts et al., 2008) and, although a Transcription, translation and subsequent protein mod- detailed account of gene expression is beyond the scope ification represent the transfer of genetic information of this review, we will briefly summarize the major from the archival copy of DNA to short-lived messenger stages to place the topic of the review, how epigenetics RNA, usually with subsequent production of protein. interacts with gene expression, in context. The initial step Although all cells in an organism contain essentially the in gene expression is the transcription of the DNA same DNA, cell types and functions differ because of molecule into an exact RNA copy. To initiate transcrip- qualitative and quantitative differences in their gene tion, RNA polymerase binds to a particular region of the expression, and control of gene expression is therefore DNA (the promoter) and starts to make a strand of at the heart of differentiation and development. The mRNA complementary to one of the DNA strands. Post- patterns of gene expression that characterize differen- transcriptional processing is critical: a methylated tiated cells are established during development and are guanosine ‘cap’ is added to the 50end of the transcribed maintained as the cells divided by mitosis. Thus, in RNA whereas splicing of the mRNA occurs via a step- addition to inheriting genetic information, cells inherit wise series of cleavage and ligation events that remove information that is not encoded in the nucleotide intron sequences and bring exons together in an sequence of DNA, and this has been termed epigenetic appropriate manner. Following splicing, the 30 terminus information. Epigenetics has been defined as ‘the study of the mRNA is cleaved and a string of adenosine of mitotically (and potentially meiotically) heritable residues, known as a polyA tail, is added in preparation alterations in gene expression that are not caused by for mRNA transport from the nucleus to the cytoplasm. changes in DNA sequence’ (Waterland, 2006). However, At this stage, the mRNA is ready to engage with some definitions of epigenetics are broader than this ribosomes for translation. In translation, polypeptides and do not necessarily encompass the requirement for are synthesised in a sequential stepwise fashion from heritability. For example, the US National Institutes of N terminus to C terminus via three distinct steps— Health (2009) in their recent epigenomics initiative state initiation, elongation and termination. After initiation, that ‘epigenetics refers to both heritable changes in gene the genetic code is read in triplets of nucleotides (codons) activity and expression (in the progeny of cells or of specified by the mRNA and the specified amino acids are individuals) and also stable, long-term, alterations in the assembled during the elongation process and attached transcriptional potential of a cell that are not necessarily via a peptidyl transferase reaction, resulting in the heritable’. Regardless of the exact definition, the formation of a peptide bond and the elongation of the epigenetic processes that stably alter gene expression peptide chain. Termination of translation occurs when patterns (and/or transmit the alterations at cell division) one of the termination codons (UAG, UAA and UGA) are thought to include: (1) cytosine methylation; (2) post- signals the release of a completed polypeptide chain. The translational modification of histone proteins and remo- ribosome then disengages from the mRNA and the delling of chromatin; and (3) RNA-based mechanisms. ribosomal subunits dissociate, ready to start the cycle again. The generated protein may undergo several post- Correspondence: Dr CM Nolan, UCD School of Biology & Environmental translational modifications before it is used in its Science, Belfield, Dublin 4, Ireland. E-mail: [email protected] dedicated role. Received 8 April 2010; accepted 12 April 2010; published online 12 The above description is a somewhat simplistic outline May 2010 of gene expression but in reality it is far from simple. Epigenetics and gene expression ER Gibney and CM Nolan 5 Numerous regulatory steps maintain the integrity of the recent work (Illingworth et al., 2008), however, suggests process and work with external factors to control each that about half of the CpG islands in the genome are not stage. Epigenetic processes, including DNA methylation associated with annotated promoters, but are located and histone modification, are thought to influence gene within genes (intragenically) or in intergenic locations. It expression chiefly at the level of transcription; however, is suggested that the latter CpG islands may mark the other steps in the process (for example splicing and transcription start sites of non-coding RNAs (Illingworth translation) may also be regulated epigenetically. et al., 2008). Either way, CpG islands are thought to have The following paper will outline the role epigenetics a major role in control of gene expression. is believed to have in influencing gene expression. In vertebrates, over 80% of CpG dinucleotides located outside of CpG islands are commonly methylated (Miranda and Jones, 2007; Nafee et al., 2008; Delcuve DNA methylation and epigenetic regulation et al., 2009). In contrast, CpGs within CpG islands are of gene expression generally not methylated or have relatively low levels of methylation (Miranda and Jones, 2007; Nafee et al., 2008; 0 Methylation of the 5 -position of cytosine residues is a Delcuve et al., 2009). In keeping with this, approximately reversible covalent modification of DNA, resulting in half of all transcribed genes have CpG islands within production of 5-methyl-cytosine (Newell-Price et al., their coding regions, and these are reported to include all 2000) and approximately 3% of cytosines in human genes that are widely expressed and less than half of DNA are methylated (Nafee et al., 2008). In mammals, those that are expressed in a tissue-specific manner 0 cytosine methylation is restricted to those located 5 to a (Nafee et al., 2008). guanosine (commonly annotated as CpGs, where the intervening ‘p’ represents the phosphodiester bond linking cytosine- and guanosine-containing nucleotides) DNA methyltransferases (DNMTs) (Razin and Cedar, 1991; Weber and Schu¨ beler, 2007). Cells have the ability to both methylate and demethylate These methyl groups allow normal hydrogen bonding DNA and this in turn is reported to influence specific (Figure 1) and project into the major groove of DNA, gene expression (Wolfe, 1998; Ashraf and Ip, 1998; Kim changing the biophysical characteristics of the DNA. et al., 2009). DNA methyltransferases (DNMTs) are the They are purported to have two effects: they inhibit the family of enzymes responsible for DNA methylation recognition of DNA by some proteins while they (Nafee et al., 2008; Kim et al., 2009; Delcuve et al., 2009) facilitate the binding of other proteins to the DNA (Figure 2). To date, four DNMTs have been identified in (Prokhortchouk and Defossez, 2008). In general, DNA mammals: DNMT1, DNMT2, DNMT3a and DNMT3b methylation is associated with gene repression (Miranda (Weber and Schu¨ beler, 2007). DNMT1 maintains DNA and Jones, 2007; Weber and Schu¨ beler, 2007). As DNA methylation during replication by copying the methyla- methylation patterns can be maintained following DNA tion pattern of the parent DNA strand onto the newly replication and mitosis (see DNA methyltransferases synthesized strand (Newell-Price et al., 2000; Kim et al., section below), this epigenetic modification is also 2009). DNMT3a and DNMT3b are responsible for de novo associated with inheritance of the repressed state. DNA methylation, targeting unmethylated CpG dinu- With four nucleotides (A, T, C and G), DNA contains cleotides (Newell-Price et al., 2000; Wang et al., 2005; 16 dinucleotide-pair possibilities. The CpG pairing Suzuki et al., 2006; Hervouet et al., 2009), as well as occurs at a lower than expected frequency throughout working

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