Triantaphyllopoulos et al. Epigenetics & Chromatin (2016) 9:31 DOI 10.1186/s13072-016-0081-5 Epigenetics & Chromatin REVIEW Open Access Epigenetics and inheritance of phenotype variation in livestock Kostas A. Triantaphyllopoulos1*, Ioannis Ikonomopoulos2 and Andrew J. Bannister3 Abstract Epigenetic inheritance plays a crucial role in many biological processes, such as gene expression in early embryo development, imprinting and the silencing of transposons. It has recently been established that epigenetic effects can be inherited from one generation to the next. Here, we review examples of epigenetic mechanisms governing animal phenotype and behaviour, and we discuss the importance of these findings in respect to animal studies, and livestock in general. Epigenetic parameters orchestrating transgenerational effects, as well as heritable disorders, and the often-overlooked areas of livestock immunity and stress, are also discussed. We highlight the importance of nutrition and how it is linked to epigenetic alteration. Finally, we describe how our understanding of epigenetics is underpinning the latest cancer research and how this can be translated into directed efforts to improve animal health and welfare. Keywords: Epigenetic, DNA methylation, Acetylation, Histone, Transcription, Transgenerational, Inheritance, Imprinting, Nutrition, Livestock Background the heritability of complex traits and diseases. In turn The term epigenetics was coined in the 1940s by Conrad this would serve to improve breeding and the genetics Waddington and applied to the possible causal mecha- of livestock. Indeed, livestock genetics is currently ben- nisms acting on the genes that govern phenotypic out- efiting from massive amounts of genomic information come. Huxley later refined this definition as he realized (e.g. arrays that genotype more than 500K SNPs along that the variation in specification of cellular phenotype the bovine genome) that are being incorporated into the was not necessarily gene sequence related [1]. Since then, prediction of genetic advantage, providing higher accu- the concept and definition of epigenetics has gradually racy [5] and leading to important changes in the animal evolved, slowly diverging from the definition originally breeding industry [6]. However, it is now clear that in prescribed by Waddington [2]. It explains how expres- addition to DNA sequence information, epigenetic infor- sion of a gene might be changed and stably maintained by mation also determines the overall phenotype (Fig. 1). modifications (of DNA and/or histones) without affect- Epigenetic processes generate the epigenome and ing the nucleotide sequence of the gene itself [3]. The involve DNA methylation, chromatin remodelling, his- ‘memory’ of such activity is transferred between cell gen- tone modifications, regulation of gene expression by non- erations through mitosis and between organismal gener- coding RNAs, genome instability and any other force that ations through meiosis [4]. modifies animal phenotype (for review see [7–9]). These Epigenetics has the potential to be very useful in ani- processes alter gene expression, and they can affect cell mal breeding, as it may provide information relating to fate and phenotype plasticity as well as behaviour. Vari- ous molecular mechanisms are involved, including par- amutation, bookmarking, imprinting, gene silencing, *Correspondence: [email protected] 1 Department of Animal Breeding and Husbandry, Faculty of Animal transposon silencing, X chromosome inactivation, posi- Science and Aquaculture, School of Agricultural Production, Infrastructure tion effect, reprogramming, transvection and maternal and Environment, Agricultural University of Athens, 75 Iera Odos St., effects [10–20]. 11855 Athens, Greece Full list of author information is available at the end of the article © 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Triantaphyllopoulos et al. Epigenetics & Chromatin (2016) 9:31 Page 2 of 18 PHENOTYPE Non-genetic ‘inheritance’ Heterochromatin Euchromatin HDM HIGHLY HMT Me Me DYNAMIC Me Remodeling K9 K9 Me HMT K36 complex TSS Ac K36 CTCF P HDM Boundary Me Me Element Ac Ac K4 K27 K27 Me K4 Inactive genes Me histone Me Me HAT Me Active genes DNA methylation at CpGs variants Hypomethylated DNA Hypoacetylated histones Hyperacetylated histones H3K9me3 and H3K27me3 DNMT HDAC H3K4me3 and H3K36me3 HMT: Histone methyltransferase HDM: Histone demethylase HAT: Histone acetyltransferase Social Pathological HDAC: Histone deacetylase Me DNA CpG methylation ‘Environmental’ Nutrients Toxins Me Histone methylation Signaling Ac Histone acetylation Physiological Behavioural P Histone phosphorylation Fig. 1 Chromatin modifications and remodelling events in livestock. Different environmental exposures trigger signalling pathways, which affect chromatin structure, thereby affecting gene expression leading to altered phenotypic attributes (phenotype) Importantly, the relationship between epigenetics and the molecular aspects that regulate the expression of cer- phenotype appears more evident in disease. For instance, tain genes or genomic regions, sometimes as a response aberrant epigenetic pathways have been identified in to external environmental factors, as described in later atherosclerosis [21], osteoarthritis [22], lupus erythema- sections. tosus [23], imprinting disorders [24], neuropsychiatric disorders [25] and improper gene inactivation in cancer Epigenetic mechanisms [26]. Epigenome abnormalities related to developmental Epigenetic mechanisms include, but are not limited to, disorders and late onset adult diseases such as metabolic DNA methylation (predominantly at CpG dinucleotides), and mental disorders have also been reported [27]. Epi- post-translational modifications (PTMs) of histones, non- genetic mechanisms in livestock have mainly focused on coding RNAs (ncRNAs) and chromatin remodelling (Fig. 1). Triantaphyllopoulos et al. Epigenetics & Chromatin (2016) 9:31 Page 3 of 18 DNA methylation enzymes and associated factors [7, 41]. Although histone DNA methylation at CpG dinucleotides involves the modifications influence transcription, since chromatin is addition of a methyl group to the 5′ position of the cyto- ubiquitous, the modifications also affect all DNA processes sine pyrimidine ring to generate 5-methylcytosine (5mC) including DNA repair, replication and recombination [7]. (Fig. 1). Cytosine methylation also occurs to a lesser Chromatin modifications function in two non-mutu- extent in non-CpG contexts [28]. Very recently, mamma- ally exclusive ways. The modifications may directly affect lian genomes have been shown to also possess adenosine chromatin structure, or they may provide dynamic bind- methylation, although the physiological consequence of ing platforms for proteins with specific binding domains. this remains unclear. Nevertheless, modifications involv- An example of the former is provided by histone acety- ing DNA methylation and alkylation damage of nucleic lation that neutralizes a lysine’s positive charge, thereby acids are tightly linked with many diseases [29]. disrupting electrostatic interactions. This would facili- CpG methylation is widespread in mammals and func- tate chromatin in adopting a less compact state, con- tions directly or indirectly at multiple levels to gener- sistent with histone acetylation being found at active ally suppress gene transcription. It is also a fundamental genes (Fig. 1). Moreover, histone acetyltransferases func- mechanism underlying transposon silencing, X chromo- tion as transcriptional coactivators and deacetylases as some inactivation and gene imprinting [30–35], and at repressors. A modification that creates a docking site least in part, these effects are due to its link to hetero- for a protein is exemplified by trimethylation of H3K9 chromatin formation and maintenance. It is performed (H3K9me3). This heterochromatic mark is specifically by DNA methyltransferases (DNMTs) and removed bound by the chromodomain of heterochromatin protein via a pathway involving specific enzymes, for example HP1, thereby facilitating the maintenance of heterochro- ten-eleven translocation methylcytosine dioxygenase 1 matin [42]. (TET1), which catalyses conversion of 5mC to 5-hydroxy- methylcytosine (5hmC). This has been proposed as the Non‑coding RNA initial step of active DNA demethylation in mammals Although DNA methylation and histone modifications [36]. It is well established, that dramatic CpG methylation are the most studied epigenetic mechanisms, other epi- changes occur during early development [37, 38]. genetic processes also participate in regulating gene In contrast to CpG methylation in gene promoters, function. An important example is non-coding RNA- methylation in the body of genes can actually lead to mediated regulation of gene expression and chromatin transcriptional activation. Furthermore, differential DNA remodelling [35] (Fig. 1). The control and nucleation of methylation occurs across distinct