Introduction
In the past, it was widely believed that all of an organism’s functions were controlled by genetic information contained in 25,000–30,000 genes throughout the genome. However, these genes account for just 5% of the total, with the remaining 95% governed by epigenetic information present in the form of the ‘epigenome’, which dictates how, when and where the information existing in the genome should be used in the form of a set of instructions known as epigenetic marks (Satheesha et al., Reference Satheesha, Nagaraja, Yathish, Jayashree, Kotresh, Sahadev and Kumar2020).
A multilayer interplay between the genome, epigenome, environmental variables and other non-genetic components results in phenotypic outcome (Ibeagha-Awemu and Khatib, Reference Ibeagha-Awemu and Khatib2023). A shift from genotype + environment = phenotype to genotype + epigenotype + environment = specific phenotype, claiming that genotype and phenotype were linked by a complex set of genetic and non-genetic developmental processes known as the epigenotype (Waddington, Reference Waddington2012). Waddington coined the term ‘epigenetic landscape’. Epigenetics is typically defined as the study of heritable changes in gene function that occur without a change in the DNA sequence (Rubio et al., Reference Rubio, Hernández-Cruz, Rogel-Ayala, Sarvari, Isidoro, Barreto and Pedraza-Chaverri2023; Zhang et al., Reference Zhang, Cheng, Wang, Jiao, Yang and Wang2019a). Several molecular processes, such as paramutation, bookmarking, imprinting, gene silencing, transposon silencing, X chromosomal inactivation, position effect, reprogramming, transvection and maternal effects are at play (Triantaphyllopoulos et al., Reference Triantaphyllopoulos, Ikonomopoulos and Bannister2016). Understanding and employing epigenetic mechanisms may help with improving livestock productivity and disease resistance, as well as understanding quantitative traits (Ibeagha-Awemu and Zhao, Reference Ibeagha-Awemu and Zhao2015; Ibeagha-Awemu and Khatib, Reference Ibeagha-Awemu and Khatib2017; Banta and Richards, Reference Banta and Richards2018; Panzeri and Pospisilik, Reference Panzeri and Pospisilik2018).
Recent studies have further advanced our understanding of epigenetic mechanisms and highlighted the role of non-coding RNAs, such as microRNAs and long non-coding RNAs, in epigenetic regulation (Zhang et al., Reference Zhang, Wang, Zhu, Dong, Cheng, Yin and Shen2019b). These non-coding RNAs have been shown to interact with the epigenetic machinery and modulate gene expression patterns. Additionally, studies have explored the impact of environmental factors, such as nutrition and stress, on epigenetic modifications and their transgenerational effects and paternal stress has the potential to alter an offspring’s phenotype by means of causing molecular, hormonal, somatic and behavioural alterations. A changed spectrum of regulatory non-coding RNAs in spermatozoa is one putative mechanism for the transmission of paternal effects to offspring. (Malysheva et al., Reference Malysheva, Pivina, Ponomareva and Ordyan2023). Paternal transgenerational nutritional epigenetic regulation was a substitute for antibiotics (Li et al., Reference Li, Wang, Liu, Chen, Qiao, Yang and Wu2022a).
Furthermore, advancements in high-throughput sequencing technologies have enabled comprehensive profiling of epigenetic marks across the genome. Techniques such as ChIP (Chromatin immunoprecipitation) sequencing, ATAC (Assay for transposase-accessible chromatin) sequencing and bisulfite sequencing have provided valuable insights into the distribution and functional significance of epigenetic marks in various species (Ran et al., Reference Ran, He, Han, Wang, Wang, Yue and Wang2023; Fan et al., Reference Fan, Liang, Deng, Zhang, Zhang, Zhang and Wang2020). These technological advancements have facilitated the identification of specific epigenetic modifications associated with gene regulation and phenotype variation.
This review aims to provide an in-depth exploration of epigenetics and its role in livestock breeding. It will examine the mechanisms of epigenetic regulation, the impact of epigenetic modifications on gene expression and phenotype and their implications for improving livestock traits. Additionally, it will discuss the challenges and opportunities associated with incorporating epigenetic knowledge into breeding strategies, ultimately highlighting the potential of harnessing epigenetics for enhancing livestock productivity and adaptability.
Epigenome dynamics in livestock: influences and implications
The epigenome is made up of several interconnected regulatory components like DNA methylation, histone modification, chromatin remodelling, non-coding RNA and nuclear matrix interactions that define phenotypic variation in addition to what the DNA sequence encodes (Dobersch et al., Reference Dobersch, Rubio, Singh, Günther, Graumann, Cordero, Castillo-Negrete, Huynh, Mehta, Braubach, Cabrera-Fuentes, Bernhagen, Chao, Bellusci, Günther, Preissner, Kugel, Dobreva, Wygrecka, Braun, Papy-Garcia and Barreto2021; Zhang et al., Reference Zhang, Wang, Zhu, Dong, Cheng, Yin and Shen2019b) (Figure 1A). These epigenetic marks play a crucial role in influencing gene expression patterns and are transmitted through mitosis, providing instructions on how genetic information should be utilized. The epigenome is known to exhibit remarkable plasticity throughout an organism’s lifespan, influenced by intricate interplay between genetic factors and environmental cues (Cavalli and Heard, Reference Cavalli and Heard2019; Norouzitallab et al., Reference Norouzitallab, Baruah, Vanrompay and Bossier2019). Furthermore, the study of non-coding RNAs, such as microRNAs, in livestock has revealed their role in post-transcriptional gene regulation and their potential as epigenetic regulators. MicroRNAs have been implicated in regulating important biological processes in livestock, including muscle development, milk production and immune response (Miretti et al., Reference Miretti, Lecchi, Ceciliani and Baratta2020; Dysin et al., Reference Dysin, Barkova and Pozovnikova2021).
(A) Diverse array of epigenetic marks in the cell epigenome, (B) DNA methylation: An epigenetic modification regulating gene expression, (C) epigenetic modifications: Regulation of gene expression through histone methylation and histone acetylation, (D) mechanism of histone ubiquitination in gene expression control, (E) regulatory roles of microRNA and lncRNA: Mechanisms of action in gene expression control.
Mechanism of epigenetic expression
DNA methylation in livestock: mechanisms and functional significance
DNA methylation is a crucial epigenetic alteration for preservation of genomic integrity and control gene expression. Gene expression is impacted by DNA methylation but not the nucleotide sequence or makeup. DNA methyltransferases (DNMTs) are enzymes that covalently transfer a methyl group to the C5 position of cytosine to generate 5-methylcytosine (5mC), most typically at the dinucleotide sequence CG (mCG) (Wang et al., Reference Wang, Bissonnette, Dudemaine, Zhao and Ibeagha-Awemu2021). DNA methylation in eukaryotes is mediated by DNMTs. CpG (cytosine-phosphate-guanosine) islands, which are frequently found inside the promoter of protein-coding genes and housekeeping genes, are defined as DNA portions that are longer than 200 base pairs and exhibit a CG:GC ratio greater than 0.6 (Wang et al., Reference Wang, Bissonnette, Dudemaine, Zhao and Ibeagha-Awemu2021). De novo DNMT activity or DNMTs inhibition can both lead to methylation reprogramming. Ten-eleven translocation (TET) enzymes catalyse the oxidation of 5mC, forming several intermediates such as 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine before its complete conversion to cytosine (Rasmussen and Helin, Reference Rasmussen and Helin2016). Methylation of the gene promoter region can cause transcriptional silence, hampering gene expression (Zhang et al., Reference Zhang, Sheng, Hu, Li, Cai, Ma and Ma2023)
The genomic landscape of 5mC results from the continuous activity of both DNA methylation and demethylation processes, creating a dynamic equilibrium that can be changed in response to stimuli, such as changes in the cell’s external environment. The importance of maintaining an appropriate equilibrium of DNA methylation is underscored by the correlation between the loss of 5mC and genomic instability and cancer, while the gain of 5mC has been linked to a number of congenital defects and other diseases (Martin and Fry, Reference Martin and Fry2018). Changes in nutritional status and environmental exposure to a variety of agents can alter patterns of genomic DNA methylation, which in turn affects the structure of chromatin and the expression of genes related to disease (Martin and Fry, Reference Martin and Fry2018; Zhang et al., Reference Zhang, Sheng, Hu, Li, Cai, Ma and Ma2023). DNA methylation levels are influenced by RNA interference, aberrant DNA methyltransferase, histone methylation, viral infection, early environmental stimulation, temperature and dietary supply (Zhang et al., Reference Zhang, Sheng, Hu, Li, Cai, Ma and Ma2023).
The discovery of DNA methylation in calf thymus cells by Hotchkiss in 1948 marked a significant milestone in understanding this epigenetic modification (Jurkowska et al., Reference Jurkowska, Jurkowski and Jeltsch2011). DNMT1 maintains methylation pattern during DNA replication (Edwards et al., Reference Edwards, Yarychkivska, Boulard and Bestor2017; Luo et al., Reference Luo, Hajkova and Ecker2018; Schmitz et al., Reference Schmitz, Lewis and Goll2019), while DNMT3a and DNMT3b are de novo methyltransferases required for mammalian genome imprinting (Veland et al., Reference Veland, Lu, Hardikar, Gaddis, Zeng, Liu and Chen2019). DNA methylation is particularly prominent in centromeres, transposons, telomeres, gene ontology sites, enhancers, silencers and repetitive regions of the genome (Zhang et al., Reference Zhang, Sheng, Hu, Li, Cai, Ma and Ma2023). Figure 1B demonstrates visual representation of the mechanism of DNA methylation.
DNA methylation-induced epigenetics also plays a significant role on animal reproductive efficiency (Canovas et al., Reference Canovas, Ross, Kelsey and Coy2017; Jhamat et al., Reference Jhamat, Niazi, Guo, Chanrot, Ivanova, Kelsey and Humblot2020; Usman et al., Reference Usman, Ali, Wang and Yu2021; Yang et al., Reference Yang, Shuli, Yang, Lingzhao, Yahui, Han and Ge2020; Gross et al., Reference Gross, Peñagaricano and Khatib2020; Fang et al., Reference Fang, Zhou, Liu, Jiang, Bickhart, Null and Liu2019; Saeed-Zidane et al., Reference Saeed-Zidane, Tesfaye, Mohammed Shaker, Tholen, Neuhoff, Rings and Salilew-Wondim2019; Liu et al., Reference Liu, Fang, Zhou, Santos, Xiang, Daetwyler and Liu2019a; Perrier et al., Reference Perrier, Sellem, Prézelin, Gasselin, Jouneau, Piumi and Kiefer2018), growth and development (Yang et al., Reference Yang, Fan, Yan, Chen, Zhu, Tang and Tang2021; Ma et al., Reference Ma, Jia, Chu, Fu, Lei, Ding and Liang2019; Shi et al., Reference Shi, Ruan, Liu, Sun, Xu and Xu2023; Fang et al., Reference Fang, Zhao, Yu, Li, Jiang, Yang and Yu2017; Johnson and Conneely, Reference Johnson and Conneely2019), epigenetic clocks (Horvath and Raj, Reference Horvath and Raj2018; Horvath et al., Reference Horvath, Lu, Haghani, Zoller, Li, Lim and Ostrander2022;), disease resistance (de Soutello et al., Reference de Soutello, Rodrigues, Gonçalves, Bello, Pavan and Ramos2022; Zhang et al., Reference Zhang, Han, Zheng, Lin, Li, Gao and Sun2021a; Jhamat et al., Reference Jhamat, Niazi, Guo, Chanrot, Ivanova, Kelsey and Humblot2020; Usman et al., Reference Usman, Ali, Wang and Yu2021), sperm DNA methylation as biomarker of male fertility (Phakdeedindan et al., Reference Phakdeedindan, Wittayarat, Tharasanit, Techakumphu, Shimazaki, Sambuu and Sato2022; Li et al., Reference Li, Wang, Xu, Zhang and Yang2020; Costes et al., Reference Costes, Chaulot-Talmon, Sellem, Perrier, Aubert-Frambourg, Jouneau, Pontlevoy, Hozé, Fritz, Boussaha, Le Danvic, Sanchez, Boichard, Schibler, Jammes, Jaffrézic and Kiefer2022), milk production (Dong et al., Reference Dong, Yang, Zhang, Liu, Ning, Ding, Wang, Zhang, Zhang and Jiang2021), meat quality (Zhang et al., Reference Zhang, Yan, Li, Jiang, Li, Han and Sun2017a), heat stress (Livernois et al., Reference Livernois, Mallard, Cartwright and Cánovas2021; Canovas et al., Reference Canovas, Ross, Kelsey and Coy2017) and wool traits in sheep (Wang et al., Reference Wang, Hua, Cai, Ma, Yang, Zhang and Deng2023a), milk production accelerated epigenetic aging in cows by preparing epigenetic clocks (Ratan et al., Reference Ratan, Rubbi, Thompson, Naresh, Waddell, Jones and Pellegrini2023).
Wang et al. (Reference Wang, Hand, Fu, Smith and Yao2019a) reported that DNA methylation in the promoter region of the bovine KPNA7 gene in controls its restricted expression in oocytes, and demethylation of CpG sites was strongly correlated with the tissue specificity of the KPNA7 gene. Rekawiecki et al. (Reference Rekawiecki, Kisielewska, Kowalik and Kotwica2018) reported that methylation of PGR-A and PGR-B in promoter region may have an impact on the regulation of progesterone in the luteum and endometrium in cows. Ju et al. (Reference Ju, Jiang, Wang, Wang, Yang, Sun and Huang2020) reported that in E. coli-induced mastitis in cows, DNA methylation affects the transcription of protein-coding genes and miRNAs, which helps to explain the role of DNA methylation in the pathogenesis of mastitis. It also provides new target genes like CITED2, SLC40A1 and LGR4 and epigenetic markers for mastitis resistance breeding in dairy cows. S. aureus-positive cattle exhibited noticeably more methylation sites on BTA 11 than S. aureus-negative controls, suggesting that DNA methylation may play a regulatory role in the immune response to S. aureus mastitis (Song et al., Reference Song, He, Zhou, Zhang, Li and Yu2016; Chen et al., Reference Chen, Wu, Sun, Dong, Wang, Zhang, Xiao and Dong2019a; Zhang et al., Reference Zhang, Wang, Jiang, Hao, Ju, Yang and Zhu2018a; He et al., Reference He, Song, Zhang, Li, Song, Zhang and Yu2016; Wang et al., Reference Wang, Xue, Liu, Liu, Hu, Qiu and Lei2016).
Heat stress also alter the DNA methylation patterns in the liver and mammary gland of dairy cows, affecting milk production and immune response (Dvoran et al., Reference Dvoran, Nemcova and Kalous2022; Qin et al., Reference Qin, Scicluna and van der Poll2021). Additionally, social stress in pigs has been associated with changes in DNA methylation and gene expression in the hypothalamus, influencing behaviour and stress response (Corbett et al., Reference Corbett, Luttman, Wurtz, Siegford, Raney, Ford and Ernst2021).
Histone modifications in livestock traits and biological processes
One important class of chromatin modifications known as histone modifications is in charge of the epigenetic control of gene expression. Under the influence of related enzymes, histones go through a variety of modification processes like as methylation, acetylation, phosphorylation, sumoylation (covalent conjugation of small ubiquitin-like modifier (SUMO) family of proteins to lysine residues in target substrates via an enzymatic cascade) (Huang et al., Reference Huang, Yang and Lin2024) and ubiquitination involved in regulation of DNA damage and transcriptional activities (Zhang et al., Reference Zhang, Zhao, Lv, Wang, Feng, Zou and Jiao2020; Alhamwe et al., Reference Alhamwe, Khalaila, Wolf, von Bülow, Harb, Alhamdan, Hii, Prescott, Ferrante, Renz, Garn and Potaczek2018; Shanmugam et al., Reference Shanmugam, Arfuso, Arumugam, Chinnathambi, Jinsong, Warrier and Lakshmanan2018). Different modifications are linked to the activation or repression of gene expression. The most significant histone modifications, which mainly affect lysine residues in histone H3, are methylation and acetylation (Zhang et al., Reference Zhang, Zhao, Lv, Wang, Feng, Zou and Jiao2020).
Histone acetylation at particular amino acids, such as histone 3 lysine 9 acetylation, or H3K9Ac, is typically linked to active chromatin. Histone deacetylases (HDACs) remove it, whereas histone acetyltransferases (HATs) mediate it. Additionally, histone methylation takes place at particular amino acids, such as H3 lysine 27 trimethylation, abbreviated H3K27me3, or H3 lysine 4 trimethylation, abbreviated H3K4me3, which can affect the expression of genes in ways that are both repressive and activating. Histone methyltransferases (HMTs), which are mostly represented by histone lysine demethylases (KDMs), mediate both histone methylation and demethylation (Zhang et al., Reference Zhang, Zhao, Lv, Wang, Feng, Zou and Jiao2020).
Histone modifications play a crucial role in regulating gene expression by altering chromatin structure and influencing the accessibility of DNA to transcription factors and other regulatory proteins (Millán-Zambrano et al., Reference Millán-Zambrano, Burton, Bannister and Schneider2022).
In various livestock species, histone modifications have been linked to embryonic development, muscle development and differentiation, adipocyte differentiation, milk production traits like milk fat yield and protein yield in cattle (Luo et al., Reference Luo, Yu, Chang, Tian, Zhang and Song2012), meat quality traits like intramuscular fat deposition in pigs (Grade et al., Reference Grade, Mantovani and Alvares2019) immune response and stress response in livestock and poultry (Stachecka et al., Reference Stachecka, Kolodziejski, Noak and Szczerbal2021; Chanthavixay et al., Reference Chanthavixay, Kern, Wang, Saelao, Lamont, Gallardo, Rincon and Zhou2020; Xue et al., Reference Xue, Qiu, Liu, Gan, Tan, Xie and Ye2021).
Histone methylation: regulation of gene expression and development
The regulation of histone methylation patterns in livestock species helps orchestrate gene expression programmes that are essential for various biological processes, including growth, development, reproduction and immune response (Millán-Zambrano et al., Reference Millán-Zambrano, Burton, Bannister and Schneider2022).
The specific histone methylation marks are associated with important traits and developmental processes in livestock species like H3K4 trimethylation (muscle development and growth) (Jin et al., Reference Jin, Peng and Jiang2016), H3K36 methylation (embryonic development and cellular differentiation), which are critical processes for proper organ development and tissue specialization (Li et al., Reference Li, Zhang, Xie, Liu, Fei, Huang and Zhou2022b) and H3K27 trimethylation in subclinical mastitis caused by Staphylococcus aureus (He et al., Reference He, Song, Zhang, Li, Song, Zhang and Yu2016), reproduction and development of oocytes, embryos and preimplantation (H3K4me3 and H3K9me2) (Wu et al., Reference Wu, Chen, Sun, Dong, Wang, Chen and Dong2020), spermatogenesis in goat (Zheng et al., Reference Zheng, Zhai, Li, Wu, Zhu, Wei and Hua2016).
Histone acetylation: modulation of chromatin structure and transcriptional activation
Histone acetylation is a crucial epigenetic modification that plays a significant role in livestock by regulating gene expression and influencing various biological processes like mastitis and metritis by H3 acetylation (Chen et al., Reference Chen, Wu, Sun, Dong, Wang, Zhang, Xiao and Dong2019b), reproduction and preimplantation (Wu et al., Reference Wu, Chen, Sun, Dong, Wang, Chen and Dong2020), in vitro maturation of bovine oocytes (Pontelo et al., Reference Pontelo, Rodrigues, Kawamoto, Leme, Gomes, Zangeronimo and Dode2020), role of H3K27ac3 in bovine rumen epithelial function and development (Kang et al., Reference Kang, Li, Liu, Baldwin, Liu and Li2023), adipogenesis and fat deposition in pigs for meat quality traits (Stachecka et al., Reference Stachecka, Kolodziejski, Noak and Szczerbal2021). Figure 1C demonstrates visual representation of the mechanism of histone methylation and histone acetylation.
Histone ubiquitination: implications for DNA damage response and genomic stability
Histone ubiquitination is an important epigenetic modification that has been extensively studied in livestock species. It primarily occurs at H2A and H2B histone proteins and involves the covalent attachment of ubiquitin monomers to lysine residues after translation. The process of histone ubiquitination is carried out through a series of enzymatic steps involving ubiquitin activating enzymes (E1s), ubiquitin conjugating enzymes (E2s) and ubiquitin ligases (E3s). Conversely, deubiquitinating enzymes (DUBs) are responsible for removing ubiquitin from histones (Figure 1D) (Yi et al., Reference Yi, Zimmerman, Manandhar, Odhiambo, Kennedy, Jonáková and Sutovsky2012).
Histone ubiquitination revealed significant association with spermatogenesis and bull fertility (Sutovsky, Reference Sutovsky2018), histone H2B mono-ubiquitination with spermatogenesis and male fertility in pigs (Yi et al., Reference Yi, Zimmerman, Manandhar, Odhiambo, Kennedy, Jonáková and Sutovsky2012), reproductive processes, like cell cycle, oocyte maturation, oocyte-sperm binding and early embryonic development (Wang et al., Reference Wang, Zhou, Ding, Yin, Ye and Zhang2022), HSCARG (cell proliferation), a novel regulator of H2A ubiquitination by downregulating PRC1 ubiquitin E3 ligase activity (Hu et al., Reference Hu, Li, Zhang and Zheng2014), apoptosis, cellular stress response and damage mechanisms (Gao et al., Reference Gao, Cui, Bao, Hao, Piao and Gu2023; Song et al., Reference Song, Shen, Liu, Yang, Xie, Guo and Wang2022), early embryonic development (El-Saafin et al., Reference El-Saafin, Devys, Johnsen, Vincent and Tora2022).
Histone phosphorylation: impact on cell cycle progression
Histone phosphorylation also modulates gene expression, particularly during cellular processes such as cell cycle progression, cellular differentiation and response to DNA damage, regulation of reproductive processes (gametogenesis and embryonic development) in various livestock species. Histone phosphorylation (H3S10) has been shown to be dynamically regulated during oocyte maturation and early embryonic development in dairy cows and phosphorylation of H2AS1 regulates expression of immune-related genes in pigs and disease resistance in livestock (Herchenröther et al., Reference Herchenröther, Wunderlich, Lan and Hake2023).
Livestock-specific histone modifications
Lysine crotonylation is involved in the identification of active sex chromosome-associated genes in post-meiotic male germ cells (Liu et al., Reference Liu, Zhou, Chen and Cheng2017a), lysine crotonylation and 2-hydroxyisobutyrylation plays important role in ovarian development in piglets (Yang et al., Reference Yang, Li, Yu and Peng2023) and parasite development like Toxoplasma gondii (Yin et al., Reference Yin, Jiang, Zhang, Wang, Sang, Feng and Chen2019). Histone neddylation is another important modification observed in livestock species and plays important role in DNA damage repair processes and maintains genome integrity (Xu et al., Reference Xu, Wang, Hu, Quan, Chen, Cao and He2010). Citrullination, the conversion of arginine residues to citrulline, can also occur on histone H3 in livestock and serve as a unique prognostic marker in patients with advanced cancer (Wang et al., Reference Wang, Zhang, Zheng, Li, Wang and Zeng2020a) and histone lactylation plays important role in mammary gland inflammation in dairy cows (Wang et al., Reference Wang, Wang, Meng, Ma, Wei, Huo and Shen2023b).
non-coding (nc) RNA in livestock
ncRNAs play significant regulatory functions in chromatin modification and gene expression that affect the health and productivity of livestock (Do and Ibeagha-Awemu, Reference Do and Ibeagha-Awemu2017; Benmoussa et al., Reference Benmoussa, Laugier, Beauparlant, Lambert, Droit and Provost2020). A variety of small RNAs, including microRNA (miRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), endogenous small interfering RNA (siRNA), and PIWI-interacting RNA (piRNA), as well as long ncRNA (lncRNA) types with a length longer than 200 nucleotides make up the cellular ncRNA repertoire. A subcategory of lncRNAs is the class of pseudogenes, which mimic protein-coding genes but lack their protein-coding function as a result of mutations (Weikard et al., Reference Weikard, Demasius and Kuehn2017, Dong et al., Reference Dong, Xu, Liu, Ponnusamy, Zhao, Zhang, Wang, Li and Wang2018). lncRNAs control histone or DNA modification, primarily methylation and acetylation, to control epigenetic modification primarily in the nucleus, which controls gene transcription at the transcriptional level (Jain et al., Reference Jain, Xi, McCarthy, Allton, Akdemir, Patel and Barton2016).
A potential relevance of identified lncRNAs in livestock regulating pigmentation processes (Weikard et al., Reference Weikard, Hadlich and Kuehn2013), meat quality traits (Billerey et al., Reference Billerey, Boussaha, Esquerré, Rebours, Djari, Meersseman, Klopp, Gautheret and Rocha2014), bovine horn ontogenesis, horn agnesia (Allais-Bonnet et al., Reference Allais-Bonnet, Grohs, Medugorac, Krebs, Djari, Graf, Fritz, Seichter, Baur, Russ, Bouet, Rothammer, Wahlberg, Esquerré, Hoze, Boussaha, Weiss, Thépot, Fouilloux and Capitan2013), horn bud formation (Wiedemar et al., Reference Wiedemar, Tetens, Jagannathan, Menoud, Neuenschwander, Bruggmann and Drögemüller2014), bovine oocytes and early stages of embryo development (Caballero et al., Reference Caballero, Gilbert, Fournier, Gagné, Scantland, Macaulay and Robert2015), emotional behaviour in pig (Tatemoto et al., Reference Tatemoto, Pértille, Bernardino, Zanella, Guerrero-Bosagna and Zanella2023), foetal development of skeletal muscle in pig (Zhao et al., Reference Zhao, Bai, Wu, Wang, Zhang, Wang and Li2015), preimplantation process in pig (Wang et al., Reference Wang, Xue, Liu, Liu, Hu, Qiu and Lei2016), porcine testis development or spermatogenesis (Ran et al., Reference Ran, Chen, Li, Wu, Liu, He and Li2016), adipogenesis in pigs (Wei et al., Reference Wei, Wang, Xu, Wang, Xiong, Yu and Pang2015), skin development and pigmentation in goat (Ren et al., Reference Ren, Wang, Chen, Jiang, Liu, Li and Zhou2016), wool fibre diameter in sheep (Yue et al., Reference Yue, Guo, Liu, Guo, Yuan, Feng and Yang2015), muscle development in chicken (Li et al., Reference Li, Wang, Wu, Zhou, Zhu and Zhang2012), Marek’s disease virus (MDV) in chicken (Infected birds of the MD-resistant line were the only ones to have strongly expressed linc-satb1 during the latent phase of MDV infection) (He et al., Reference He, Ding, Zhan, Zhang, Han, Hu and Song2015a), lncRNA transcript pouBW1 association with growth traits in chicken (Mei et al., Reference Mei, Kang, Liu, Jia, Li, Li and Jiang2016). Arriaga-Canon et al. (Reference Arriaga-Canon, Fonseca-Guzmán, Valdes-Quezada, Arzate-Mejía, Guerrero and Recillas-Targa2014) reported that the nuclear α-globin transcript lncRNA (lncRNA-αGT) is responsible for the stage-specific activation of the adult alpha D-globin gene in chicken. Roeszler et al. (Reference Roeszler, Itman, Sinclair and Smith2012) reported that lncRNA MHN, a Z chromosome-linked region showed differential expression in male and female which contributes to the development of the gonadal and embryonic tissues in chickens.
In sheep, a muscle-specific silencer that regulates the expression of cluster DLK1-DIO3 on OAR18, resulting in the CLPG (Callipyge) phenotype (Bidwell et al. Reference Bidwell, Waddell, Taxis, Yu, Tellam, Neary and Cockett2014).
miRNAs are short RNA molecules, approximately 20–24 base pairs in length, that do not encode proteins. The binding of miRNAs to complementary sequences in the 3’-untranslated regions of target mRNAs results in the post-transcriptional regulation of both gene expression and protein translation via the inhibition of translation initiation and elongation (Saliminejad et al., Reference Saliminejad, Khorram Khorshid, Soleymani Fard and Ghaffari2019; Neethirajan, Reference Neethirajan2022). miRNAs are known to regulate the expression of genes involved in various biological processes, including signal transduction (Barbu et al., Reference Barbu, Condrat, Thompson, Bugnar, Cretoiu, Toader, Suciu and Voinea2020), cell cycle (Otto et al., Reference Otto, Candido, Pilarz, Sicinska, Bronson, Bowden and Sicinski2017), differentiation (Yao, Reference Yao2016), proliferation (Lenkala et al., Reference Lenkala, LaCroix, Gamazon, Geeleher, Im and Huang2014) and apoptosis (Shirjang et al., Reference Shirjang, Mansoori, Asghari, Duijf, Mohammadi, Gjerstorff and Baradaran2019). miRNA used as biomarkers for detection and monitoring of disease progression in animals due to their high stability in the body fluids of livestock (Correia et al., Reference Correia, Nalpas, McLoughlin, Browne, Gordon, MacHugh and Shaughnessy2017; Zhang et al., Reference Zhang, Li, Li, Li, Guo, Yao and Mi2015).
There is increasing evidence that specific miRNAs are altered in various disease states in livestock (Miretti et al., Reference Miretti, Lecchi, Ceciliani and Baratta2020) like mycoplasma bovis, bovine viral diarrhoea virus and Staphylococcus aureus (Casas et al., Reference Casas, Cai, Kuehn, Register, McDaneld and Neill2016; Taxis and Casas, Reference Taxis and Casas2017; Sun et al., Reference Sun, Aswath, Schroeder, Lippolis, Reinhardt and Sonstegard2015).which is caused by altered immunity (Lawless et al., Reference Lawless, Reinhardt, Bryan, Baker, Pesch, Zimmerman and Lynn2014), paratuberculosis (Gupta et al., Reference Gupta, Maclean, Ganesh, Shu, Buddle, Wedlock and Heiser2018), foot and mouth disease (Basagoudanavar et al., Reference Basagoudanavar, Hosamani, Tamil Selvan, Sreenivasa, Sanyal and Venkataramanan2018), heat stress (candidate miRNAs: bta-miR-21-5p, bta-miR-99a-5p, bta-miR-146b, bta-miR-145, bta-miR-2285 t, bta-miR-133a and bta-miR-29c) (Lee et al., Reference Lee, Lee, Son, Lim, Kim, Kim and Choi2020; Li et al., Reference Li, Yang, Du, Zhang, He, Hu and Zhong2018a), tumorigenesis and cancers (Gebert and MacRae, Reference Gebert and MacRae2019), microRNA-145 potent tumour suppressor (Ye et al., Reference Ye, Shen and Zhou2019), ovarian function, uterine receptivity, embryonic development and placental function (Oladejo et al., Reference Oladejo, Li, Wu, Imam, Shen, Ding and Yan2020), miR-21-3p promotes viability and proliferation of epithelial tissue in mammary gland of cattle (Kozomara et al., Reference Kozomara, Birgaoanu and Griffiths-Jones2019), miR-21-3p in endometritis (Zhang et al., Reference Zhang, Cheng, Wang, Jiao, Yang and Wang2019a), miR-185 in retained foetal membranes (Stenfeldt et al., Reference Stenfeldt, Arzt, Smoliga, LaRocco, Gutkoska and Lawrence2017), bovine mastitis (Lawless et al., Reference Lawless, Reinhardt, Bryan, Baker, Pesch, Zimmerman and Lynn2014) and Aujeszky’s disease (Timoneda et al., Reference Timoneda, Nunez-Hernandez, Balcells, Muñoz, Castello, Vera and Nunez2014).
siRNAs are involved in gene silencing, snoRNAs participate in modifications of ribosomal RNA, and lncRNAs are implicated in telomere regulation, genomic imprinting and X-chromosome inactivation. piRNAs play a role in suppressing transposons and regulating DNA methylation. Additionally, circRNAs are involved in gene transcription control and can act as sponges for RNA binding proteins (Xue et al., Reference Xue, Yang, Luo, Cho and Liu2017; Criscitiello et al., Reference Criscitiello, Kraev and Lange2020; Yuan et al., Reference Yuan, Yu, Dai, Gao, Ding, Yu and Zhang2015).
In farm animals, ncRNAs have been found to play diverse roles in different physiological processes, including disease pathogenesis, adipogenesis and milk production (Criscitiello et al., Reference Criscitiello, Kraev and Lange2020; Yuan et al., Reference Yuan, Yu, Dai, Gao, Ding, Yu and Zhang2015; Xue et al., Reference Xue, Yang, Luo, Cho and Liu2017). Only a few public databases, like LncRNAdb, ALDB v1, RNAcentral, NONCODE 2016, deepBase v2.0, etc., can be searched for deposited lncRNAs associated with livestock (Weikard et al., Reference Weikard, Demasius and Kuehn2017). Mechanism of action of microRNAs and lncRNAs is illustrated in Figure 1E, depicting their involvement in gene regulation and cellular processes in livestock species.
Transgenerational epigenetic inheritance
Epigenetic markers, such as DNA methylation, can be changed in sperm and oocytes as a result of environmental exposures. It is possible for these epigenetic modifications to be passed on through fertilization, which could have an impact on both the programming of the fetus and the phenotypic characteristics of the progeny. Transgenerational epigenetic inheritance refers to the transfer of epigenetic marks over several generations. Intergenerational epigenetic inheritance refers to the transmission of epigenetic marks over two generations (Khatib, Reference Khatib2021). According to van Otterdijk and Michels (Reference van Otterdijk and Michels2016), for inherited epigenetic changes to be deemed transgenerational epigenetic inheritance in females, the marks must be retained for three generations after the mother’s direct exposure. Epigenetic inheritance has a significant impact on phenotypic variance during the development of both an individual and their progeny (Triantaphyllopoulos et al., Reference Triantaphyllopoulos, Ikonomopoulos and Bannister2016; Nilsson et al., Reference Nilsson, Sadler-Riggleman and Skinner2018). As a result, epigenetic inheritance, including intergenerational and transgenerational inheritance, supports the idea that individual phenotype modifications may originate from environmental influences on founder generations during vital germline cell developmental stages (Nilsson et al., Reference Nilsson, Sadler-Riggleman and Skinner2018; Skinner et al., Reference Skinner, Ben Maamar, Sadler-Riggleman, Beck, Nilsson, McBirney and Yan2018). Therefore, epigenetic inheritance in farm animals involves the transmission of epigenetic biomarkers such as DNA methylation, histone modifications and ncRNAs between generations (Triantaphyllopoulos et al., Reference Triantaphyllopoulos, Ikonomopoulos and Bannister2016; Thompson et al., Reference Thompson, Nilsson and Skinner2020). Many biological processes, including gene expression throughout early embryonic development, imprinting and the silencing of transposons, depend heavily on epigenetic inheritance (Triantaphyllopoulos et al., Reference Triantaphyllopoulos, Ikonomopoulos and Bannister2016).
Radford et al. (Reference Radford, Ito, Shi, Corish, Yamazawa, Isganaitis and Ferguson-Smith2014) investigated transgenerational epigenetic inheritance in sheep caused by folate supplementation in diet of pregnant ewes during early gestation and found altered DNA methylation patterns in the offspring associated with body weight and wool quality traits in further generations. Tarrade et al. (Reference Tarrade, Panchenko, Junien and Gabory2015) revealed significant association of high-fat diet in pregnant sows and alterations in DNA methylation patterns in the offspring that are associated with metabolic disturbances and adipogenesis in the offspring and subsequent generations.
Epigenetics in livestock breeding: insights and implications
The participation of dynamic epigenetic alterations in a variety of biological processes, particularly in response to environmental stimuli, is crucial for normal growth and development (Thompson et al., Reference Thompson, Nilsson and Skinner2020). Understanding of epigenetic regulatory roles in livestock development and health is furthered by the finding of epigenomic patterns in various tissues. Epigenetic processes had significant effect on placental and embryo development of cattle (Wang et al., Reference Wang, Wang, Wang, Wang, Liang and Liu2017). According to Perrier et al. (Reference Perrier, Sellem, Prézelin, Gasselin, Jouneau, Piumi and Kiefer2018), the DNA methylome of sperm is typically less methylated than the DNA methylome of somatic tissues and the promoters and exons of hypomethylated genes in bull sperm were enriched for biological processes critical to sperm functions, such as sexual reproduction, fertilization, cell adhesion and migration, meiosis, RNA transport and signalling regulation. Furthermore, it was discovered that male fertility and associated traits are impacted by dysregulation of DNA methylation in sperm (Perrier et al., Reference Perrier, Sellem, Prézelin, Gasselin, Jouneau, Piumi and Kiefer2018; Fang et al., Reference Fang, Zhou, Liu, Jiang, Bickhart, Null and Liu2019) and histone changes, such as histone acetylation and methylation (Kutchy et al., Reference Kutchy, Menezes, Chiappetta, Tan, Wills, Kaya and Memili2018). Epigenetic alterations have an effect on bovine development, health and production, according to epigenomic profiling of somatic tissues such the liver, brain and mammary gland tissues (Kweh et al., Reference Kweh, Merriman and Nelson2019; Wang et al., Reference Wang, Wei, Shi, Khan, Fan, Wang and Yu2020b). DNA methylation controls the activity of the SIRT6 promoter during the development of bovine adipocytes (Hong et al., Reference Hong, Wang, Mei, Wang and Zan2019). Analysis of the epigenetic processes in several pig tissues, such as the brain, small intestine and longissimus dorsi muscle, revealed that these tissues have important regulatory functions during pigs’ growth and development (Su et al., Reference Su, Fan, Wu, Li, Wang, Zhang and Wang2016; Larsen et al., Reference Larsen, Kristensen and Callesen2018). Epigenetic modifications play important role in brain development (Larsen et al., Reference Larsen, Kristensen and Callesen2018), steroidogenesis and folliculogenesis (Cao et al., Reference Cao, Zhang, Wang, Tong, Avalos, Khan, Gao, Xu, Zhang, Knott and Zhang2020), nutrient metabolism in liver (He et al., Reference He, Wang, Liu, He, Che, Jin and Li2017) and bacterial colonization of preterm neonate’s intestine in pigs (Pan et al., Reference Pan, Gong, Nguyen, Zhang, Hu, Lu and Gao2018). The evolution and development of chickens are significantly influenced by epigenetic mechanisms like DNA methylation and histone modifications for example embryonic muscle development (Liu et al., Reference Liu, Han, Shen, Wang, Cui, He and Yin2019b), fatty liver syndrome of fat metabolism (Liu et al., Reference Liu, Li, Liu, Zhao, Zhang, Zheng and Wen2016), reproductive performance of inbred chickens (Han et al., Reference Han, Xue, Li, Yin, Zhang, Zhu and Zou2020). Epigenetic changes have been recognized as significant regulatory mechanisms for milk production in dairy cows and other livestock species (Ibeagha-Awemu and Zhao, Reference Ibeagha-Awemu and Zhao2015; Dechow and Liu, Reference Dechow and Liu2018; Wang et al., Reference Wang, Sun, Guan and Liu2019b). A gene closely linked to milk production called EEF1D also has its spatial expression controlled by DNA methylation (Liu et al., Reference Liu, Yang, Zhang and Jiang2017b). A significant association between different DNA methylation levels and milk-related genes, such as PPAR, RXR, and NPY, as well as genes related to milk fat, such as ACACA and SCD, in goats has been found (Zhang et al., Reference Zhang, Zhang, Ma, Jiang, Xu, Chen and Lan2017b) and puberty related genes like GnRH and KISS1 (Robaire et al., Reference Robaire, Delbes, Head, Marlatt, Martyniuk, Reynaud and Mennigen2022; Jeet et al., Reference Jeet, Magotra, Bangar, Kumar, Garg, Yadav and Bahurupi2022) and suggests that DNA methylation plays important regulatory roles in goat lactation. Epigenetic mechanisms modulates the expression of genes involved in the regulation of development of muscles (DLK1, NR4A1, TGFB3, ACSL1, RYR1, ACOX2, PPARG2, NTN1, SIX1 and MAPRE1) (Wei et al., Reference Wei, Li, Zhao, Wang, Mei, Khan and Zan2018; Cao et al., Reference Cao, Jin, Ma and Zhao2017; Fan et al., Reference Fan, Liang, Deng, Zhang, Zhang, Zhang and Wang2020), meat quality traits (TMEM8C, IGF2, FASN, CACNA1S, FADS6 and MUSTN1) in beef cattle (Fang et al., Reference Fang, Zhao, Yu, Li, Jiang, Yang and Yu2017; Chen et al., Reference Chen, Chu, Xu, Jiang, Wang, Shen, Li, Zhang, Mao and Yang2019c; Ma et al., Reference Ma, Jia, Chu, Fu, Lei, Ding and Liang2019), beef tenderness (myosin related genes like ABCA1, ABCA7 and ABCG1) in angus cattle (Zhao et al., Reference Zhao, Ji, Carrillo, Li, Tian, Baldwin and Song2020), bovine adipocyte differentiation (SIRT4) (Hong et al., Reference Hong, Wang, Mei, Wang and Zan2019) and organ development (PHF14) (Leal-Gutiérrez et al., Reference Leal-Gutiérrez, Elzo and Mateescu2020). Epigenetic mechanisms have a major impact on the egg laying performance of poultry (He et al., Reference He, Zuo, Edwards, Zhao, Lei, Cai and Song2018; Guo et al., Reference Guo, Chen, Chen, Guo, Yuan, Kang and Jiang2020; Omer et al., Reference Omer, Hu, Idriss, Abobaker, Hou, Yang and Zhao2020; Omer et al., Reference Omer, Hu, Hu, Idriss, Abobaker, Hou and Zhao2018). DNA methylation and histone acetylation were discovered to be substantially associated with cashmere production and quality traits (HOXC8 and HOTAIR gene) in goat (Wang et al., Reference Wang, Wang, Wang, Wang, Liang and Liu2017; Palazzese et al., Reference Palazzese, Czernik, Iuso, Toschi and Loi2018; Dai et al. Reference Dai, Zhang, Yuan, Ren, Han and Liu2019; Li et al. Reference Li, Li, Zhou, Gao, Ma, Chen and Wang2018b; Jiao et al. Reference Jiao, Yin, Zhao, Wang, Zhu, Wang and Bai2019). Epigenetic alterations have a substantial impact on the dynamic control of immune responses to stresses like infection (Safi-Stibler and Gabory, Reference Safi-Stibler and Gabory2020; Emam et al., Reference Emam, Livernois, Paibomesai, Atalla and Mallard2019), Mycobacterium bovis in cattle (Doherty et al., Reference Doherty, Whiston, Cormican, Finlay, Couldrey, Brady, O’Farrelly and Meade2016), Bovine viral diarrhoea (Fu et al., Reference Fu, Shi and Chen2017), mastitis (Zhang et al., Reference Zhang, Wang, Jiang, Hao, Ju, Yang and Zhu2018a; Wu et al., Reference Wu, Chen, Sun, Dong, Wang, Chen and Dong2020; Usman et al., 2016; Wang et al., Reference Wang, Wei, Shi, Khan, Fan, Wang and Yu2020b; Sajjanar et al., Reference Sajjanar, Trakooljul, Wimmers and Ponsuksili2019; Wang et al., Reference Wang, Liang, Ibeagha-Awemu, Li, Zhang, Chen and Mao2020c; Ju et al., Reference Ju, Jiang, Wang, Wang, Yang, Sun and Huang2020; Kweh et al., Reference Kweh, Merriman and Nelson2019), Scrapie (Hernaiz et al., Reference Hernaiz, Sentre, Bolea, López-Pérez, Sanz, Zaragoza and Martín-Burriel2019), porcine reproductive and respiratory syndrome virus (PRRSV) infection (Lu et al., Reference Lu, Song, Li, Li, Wang, Liu and Li2017), infectious bursal disease in chickens (Ciccone et al., Reference Ciccone, Smith, Mwangi, Boyd, Broadbent, Smith and Nair2017), New castle disease resistance (Chanthavixay et al., Reference Chanthavixay, Kern, Wang, Saelao, Lamont, Gallardo, Rincon and Zhou2020). Various epigenetically regulated gene loci and traits in Livestock and poultry are listed in Table 1.
Epigenetically regulated gene loci and traits in livestock and poultry
Environmental factors, particularly EDCs (endocrine disruptors) derived from plastic (bisphenol-A, BPA, phthalate di-2-ethylhexyl phthalate, DEHP and bisphenol-A bis-diphenyl phosphate, BDP), cause oxidative stress and lead to abnormal DNA methylation in both male and female gametes, which results in transgenerational epigenetic modifications (Selvaraju et al., Reference Selvaraju, Baskaran, Agarwal and Henkel2021; Skinner, Reference Skinner2016; Liu et al., Reference Liu, Wang, Mou, Che, Fang, Feng and Wu2017c). By inducing oxidative stress, BPA alters DNA methylation, which has an impact on male rat pup development and reproductive function (El Henafy et al., Reference El Henafy, Ibrahim, Abd El Aziz and Gouda2020). DEHP exposure during pregnancy and in ancestry has been shown to disrupt DNA methylation in the ovaries of CD-1 mice in each generation by altering the activity of enzymes like DNMT and TET, which changes the expression of genes in pathways like the sex steroid hormone synthesis pathway, the phosphoinositide 3-kinase pathway, cell cycle regulators, apoptosis, steroid hormone receptors and insulin-like growth factors (Rattan et al., Reference Rattan, Beers, Kannan, Ramakrishnan, Brehm, Bagchi and Flaws2019) necessary for ovarian cell growth, proliferation and function. Additionally, DBP exposure during embryonic development results in hypomethylation of genes essential for heart development, which results in congenital cardiac abnormalities (Hernández-Cruz et al., Reference Hernández-Cruz, Amador-Martínez, Aranda-Rivera, Cruz-Gregorio and Chaverri2022). Epigenetic modifications and their potential effects on controlling important phenotypes of agricultural importance are illustrated in Figure 2.
Epigenetic modifications and their potential effects on controlling important phenotypes of agricultural importance. Important genes proven to be epigenetically regulated by environmental factors, including nutrition, and the combined effect of these factors may have significant effects on aspects related to animal behaviour, growth and health in cattle.
Nutri-epigenomics and epigenetic regulation in livestock
Nutrients can influence gene expression via epigenetic processes. Nutritional limitations during the early developmental period may have a significant effect on DNA methylation, animal growth and health (Zhang, Reference Zhang2018b). Efforts have been focused on adapting nutritional supplements to livestock animals and their related implications in order to improve livestock health and welfare, decrease production costs and adapt to global warming (Bobeck, Reference Bobeck2020). In 2050, it’s predicted that the global population will be 9.6 billion people. Heat stress (HS) has become a significant issue for the dairy sector due to rising global temperatures and increased demand for livestock output. The impact of HS on production factors such dry matter intake, milk yield and feed efficiency have been demonstrated to be detrimental. HS has been demonstrated to negatively impact dairy cow reproduction in addition to other production-related factors. The strategic planning of nutrition and environmental factors is required for the mitigation of HS impacts on dairy cow productivity and fertility.
The Dutch famine is among the most famous examples of how nutrition may affect epigenetics and health. The intake of calories consumed was significantly lower than what is advised for human health during a difficult winter during World War II. Adult obesity, type 2 diabetes, cardiovascular disease, a susceptibility for dyslipidemias and even mental disorders were more common in fetuses born under these conditions. Surprisingly, those exposed to these circumstances displayed malnutrition-associated differentially methylated regions (P-DMRs), which are locations in the genome that have varying levels of methylation. These P-DMRs are typically found in regulatory components, especially in areas related to birth weight and LDL cholesterol levels (Goyal et al., Reference Goyal, Limesand and Goyal2019; Fernandez-Twinn et al., Reference Fernandez-Twinn, Hjort, Novakovic, Ozanne and Saffery2019). miRNAs have a key role in the harmful effects of heavy metals, especially when it comes to altered epigenetic mechanisms of gene expression in neurological illnesses. Lead (Pb) and cadmium (Cd) are two examples of heavy metals that have been linked to the onset of amyotrophic lateral sclerosis (ALS), Parkinson’s disease and Alzheimer’s disease (Genchi et al., Reference Genchi, Sinicropi, Lauria, Carocci and Catalano2020; Wallace et al., Reference Wallace, Taalab, Heinze, Tariba Lovaković, Pizent, Renieri and Buha Djordjevic2020). From a nutritional standpoint, it has been established that consumption of glucose stimulates the protein Thioredoxin-Interacting Protein (TXNIP), which then causes the development of miR-204. As a result, type 2 diabetes mellitus is facilitated by miR-204, which targets MAFA, a crucial transcription factor for insulin synthesis (Xu et al., Reference Xu, Chen, Jing and Shalev2013). Nutrition has a significant influence on epigenetic regulators and, as a result, plays a potentially important role in the control of cellular responses like oxidative stress. HS directly influences embryonic development through epigenetic control, or indirectly through decreased DMI and changes to the animal’s metabolic state (Abdelatty et al., Reference Abdelatty, Iwaniuk, Potts and Gad2018). According to Vargas et al. (Reference Vargas, Nochi, Castro, Cunha, Silva, Togawa and Franco2023) DNA methylation was low in the early stages of embryonic development but increased from the six to eight cell stage to the blastocyst stage. Furthermore, a low-protein diet in rats changed the early embryonic de novo methylation process (Abdelatty et al., Reference Abdelatty, Iwaniuk, Potts and Gad2018). In order to regulate the genome’s epigenetic state through DNA methylation and histone modifications, a subset of nutrients known as epi-nutrients are required. The proper addition of epi-nutrients during heat stress may help to control how the embryo develops. These nutrients have an impact on peri-conceptional DNA methylations, which have an impact on embryonic development, post-implantation growth and the health of the progeny. Most epi-nutrients, including folate, vitamin B-12, methionine, choline and betaine, can modify the 1-carbon metabolic pathways that are responsible of producing the main methyl donor, S-adenosylmethionine (SAM), which can directly impact DNA methylation. The epi-nutrients choline and folate are crucial for DNA methylation reprogramming during early embryonic development (Abdelatty et al., Reference Abdelatty, Iwaniuk, Potts and Gad2018). Crouse et al. (Reference Crouse, Caton, Claycombe-Larson, Diniz, Lindholm-Perry, Reynolds, Dahlen, Borowicz and Ward2022) reported that epigenetic modifiers such methionine, choline, folic acid and vitamin B12 take role in methylation responses during early embryonic development. He et al. (Reference He, Xie, Dong, Li, Li and Chen2015b) reported that supplemental dietary folic acid was effective in reversing changes in the tp53 gene expression and DNA methylation status of intrauterine growth delayed rats. Mennitti et al. (Reference Mennitti, Oliveira, Morais, Estadella, Oyama, do Nascimento and Pisani2015) reported that fat intake during development causes fatty acid desaturase gene (Fads2) transcription to change persistently in the hepatic polyunsaturated fatty acid status of offspring. According to Osorio et al. (Reference Osorio, Jacometo, Zhou, Luchini, Cardoso and Loor2016), methionine-supplemented Holstein cows had reduced levels of overall DNA methylation and hypermethylation in the promoter of a PPARA-specific DNA region. Energy restriction had a significant impact on the DNA methylation level of an IGF2 DMR in foetal beef cattle longissimus dorsi, where IGF2 expression was inversely correlated with fetus weight in Angus-Simmental crossbred cows (Paradis et al., Reference Paradis, Wood, Swanson, Miller, McBride and Fitzsimmons2017). Additionally, offspring were obese due to their mothers’ high-fat diets, and individual variances in obesity may be controlled by epigenetic changes (Keleher et al., Reference Keleher, Zaidi, Shah, Oakley, Pavlatos, El Idrissi and Cheverud2018; Glendining and Jasoni, Reference Glendining and Jasoni2019). The ability of female children to reproduce can also be impacted by dietary changes during pregnancy, which may be controlled by epigenetic changes, according to reports (Noya et al., Reference Noya, Casasús, Ferrer and Sanz2019; Shah and Chauhan, Reference Shah and Chauhan2019). In pigs, dietary changes like feed restriction, supplementation with omega-3 fatty acids, vitamin C and methyl donors have been shown to result in altered global DNA methylation patterns, which in turn affect the development of germline cells and embryos, growth and inflammatory issues in piglets and the rate at which piglets grow (Yu et al., Reference Yu, Liu, Liu, Wang, Liu, Miao and Yang2018; Zglejc-Waszak et al., Reference Zglejc-Waszak, Waszkiewicz and Franczak2019; Boddicker et al., Reference Boddicker, Koltes, Fritz-Waters, Koesterke, Weeks, Yin, Mani, Nettleton, Reecy, Baumgard, Spencer, Gabler and Ross2016). In addition, low serum concentration of galactose in neonatal piglets in response to betaine-supplemental feeding of sows was associated with inhibited expression of the GALK1 gene through DNA hypermethylation and histone trimethylation in the liver (Cai et al., Reference Cai, Yuan, Liu, Han, Pan, Yang and Zhao2017). In the promoter region of the PPAR gene, histones H3K36me3 and H4K12ac have a role in the regulation of altered lipid metabolism and growth performance after maternal genistein supplementation (Lv et al., Reference Lv, Fan, Song, Li, Liu and Guo2019) and maternal betaine supplementation affect genes linked to cholesterol and corticosteroid synthesis in offspring pullets through altered DNA methylation (Hu et al., Reference Hu, Sun, Zong, Liu, Idriss, Omer and Zhao2017; Idriss et al., Reference Idriss, Hu, Hou, Hu, Sun, Omer and Zhao2018; Abobaker et al., Reference Abobaker, Hu, Omer, Hou, Idriss and Zhao2019). Maternal nutrition during pregnancy has been shown to impact the DNA methylation patterns in offspring, which can have consequences on growth and muscle development (Amorín et al., Reference Amorín, Liu, Moriel, DiLorenzo, Lancaster and Peñagaricano2023; Liu et al., Reference Liu, Amorín, Moriel, DiLorenzo, Lancaster and Peñagaricano2021; Zhang et al., Reference Zhang, Otomaru, Oshima, Goto, Oshima, Muroya and Gotoh2021b; Sandoval et al., Reference Sandoval, Askelson, Lambo, Dunlap and Satterfield2021), energy metabolism (Muroya et al., Reference Muroya, Otomaru, Oshima, Oshima, Ojima and Gotoh2023: Muroya et al., Reference Muroya, Zhang, Kinoshita, Otomaru, Oshima, Gotoh and Gotoh2021), reproduction and fertility (Moura et al., Reference Moura, Macias-Franco, Pena-Bello, Archilia, Batalha, Silva and Fonseca2022) and disease development (Thompson et al., Reference Thompson, Nilsson and Skinner2020; Goyal et al., Reference Goyal, Limesand and Goyal2019), dietary resveratrol supplementation affect muscle fibre types and meat quality in beef cattle (Li et al., Reference Li, Liang, Mao, Yang, Luo, Qian and Zhu2022c)
Epigenetic modifications, specifically histone modifications, have been implicated in the alteration of CYP7 alpha 1 promoter in the offspring of rats subjected to a maternal low-protein diet, thereby affecting hepatic cholesterol homeostasis (Songstad et al., Reference Songstad, Kaspersen, Hafstad, Basnet, Ytrehus and Acharya2015). The health, growth and productivity of cattle could perhaps be impacted by diet-related changes in a way that has not previously been recognized (Figure 2).
Assisted reproduction technologies (ART) and epigenetics in livestock: implications for embryo development
Assisted reproductive technologies alter the embryos’ transcriptome and epigenome, which may have long-term phenotypic effects (Canovas et al., Reference Canovas, Ivanova, Hamdi, Perez-Sanz, Rizos, Kelsey and Coy2021). Assisted reproductive technology (ART) known as somatic cell nuclear transfer (SCNT) is a rapidly evolving field. It was discovered that a variety of factors regulating the biological, molecular and epigenetic events govern how effectively animals can produce SCNT-derived embryos, conceptuses and progeny (Skrzyszowska and Samiec, Reference Skrzyszowska and Samiec2021). In pre- and post-implantation cloned goat embryos, the nuclear genome of terminally differentiated somatic cells, such as pituicytes, can successfully undergo the whole processes of epigenetic remodelling and reprogramming. Deng et al. (Reference Deng, Liu, Ren, An, Wan and Wang2019) reported that transcriptional activity of Xist gene decreased significantly in lungs and brain of dead cloned does (lack of inactivation of one of the X chromosomes) and increased significantly in ear derived cutaneous fibroblast cells of live cloned does (normal inactivation of one of the X chromosomes). Deng et al. (Reference Deng, Liu, Ren, An, Wan and Wang2019) concluded increased levels of hypermethylation and transcriptional suppression of the Xist gene occurred in caprine SCNT-derived female fetuses. As a result, neither of the two X chromosomes was inactivated, or active induction of increased transcriptional activity (i.e., biallelic overexpression) of the genes localized in the loci of the paternal and maternal X chromosomes. One of the biggest hurdles deemed to be alleviating the efficiency of somatic cell cloning in mammals, including the domestic goat, is incomplete or inaccurate epigenetic reprogramming of epigenetic memory (Samiec and Skrzyszowska, Reference Samiec and Skrzyszowska2018; Yang et al., Reference Yang, Perisse, Fan, Regouski, Meyer-Ficca and Polejaeva2018). A commonly studied and acknowledged alteration of the somatic cell nuclear genome in cloned embryos is the methylation of cytosine residues in CpG islands (Deng et al., Reference Deng, Liu, Chen, Wan, Yang, Zhang, Cai, Zhou and Wang2020a; Deng et al., Reference Deng, Zhang, Cai, Liu, Zhang, Meng, Wang and Wan2020b). Han et al. (Reference Han, Deng, Mao, Luo, Wei, Meng and Zhang2018) reported enzymatic activity of ten-eleven translocation methylcytosine dioxygenase 3 (TET3) to be a crucial biological mechanism driving active DNA demethylation in preimplantation goat embryos made through somatic cell cloning. The active (i.e., DNA replication independent) demethylation of 5-methylcytosine (5-mC) residues was inhibited in 2-blastomere-stage cloned goat embryos after TET3 gene knockout. Because of this, the pluripotency-related Nanog gene’s expression was downregulated in the inner cell mass (ICM) compartment of the resulting blastocysts (Han et al., Reference Han, Deng, Mao, Luo, Wei, Meng and Zhang2018). Blastocysts exhibit sexually-dimorphic DNA methylation patterns, and in vivo embryos exhibited the highest levels of methylation (29.5%), comparable to those produced in vitro with serum, whereas in vitro embryos produced with reproductive fluids or albumin displayed lower global methylation (25–25.4%) (Canovas et al., Reference Canovas, Ivanova, Hamdi, Perez-Sanz, Rizos, Kelsey and Coy2021).The epigenetic memory profile of mammalian SCNT embryos was modified using novel and incredibly effective techniques like applying exogenous nonselective HDAC inhibitors (such as trichostatin A, valproic acid and scriptaid) and/or nonselective DNMT inhibitors (such as 5-aza-20-deoxycytidine) or selective inhibitors lysine K4 demethylases specific for histones H3 within the nucleosomal core of nuclear chromatin (such as trans-2-phenylcyclopropylamine (tranylcypromine; 2-PCPA) (Samiec et al., Reference Samiec, Romanek, Lipiński and Opiela2019).
Cytogenomic techniques for epigenetic studies in livestock
Next-generation sequencing
NGS is a useful tool for analysing the miRNA transcriptome’s complexity. In addition to advances in genome-wide association studies and metagenomics, the use of high-throughput NGS technology in livestock research has also made it possible to better understand the function of miRNAs in cattle health (Oladejo et al., Reference Oladejo, Li, Wu, Imam, Shen, Ding and Yan2020).
MinION and GridION
The direct electronic analysis of proteins, RNA, DNA and single molecules is made possible by these related technologies, which were created by Oxford Nanopore Technologies (Miretti et al., Reference Miretti, Lecchi, Ceciliani and Baratta2020). These technologies were widely employed for field diagnosis during the 2020 African swine fever outbreak in China (Jia et al., Reference Jia, Cong, Li, Yang, Sun, Parvizi and Zhao2012). ‘Crush-side genotyping’, which has been created especially for the real-time, on-farm genotyping of animals, is one potential application of this technique. Pig S. suis bacteria have been functionally characterized using MinION sequencing (antimicrobial resistance). Using the MinION technique, whole-genome generation and characterization profiling, including miRNA sequences, were effectively completed.
Ion torrent sequencing
Amplicon sequencing is only possible using ion torrent sequencing, which measures the H+ ions emitted after base incorporation. The sequencing method was used to discover microRNAs that were differentially expressed in heat-stressed Sahiwal (Deiuliis, Reference Deiuliis2016) and Frieswal breeds of cattle (Sengar et al., Reference Sengar, Deb, Singh, Raja, Kant, Sajjanar and Joshi2018). Sengar et al. (Reference Sengar, Deb, Singh, Raja, Kant, Sajjanar and Joshi2018) reported 420 miRNAs out of which 65 miRNAs showed differential expression during the hottest summer days, including bta-miR-2898, which is known to target HSPB8 (heat shock protein 22). In pigs infected with the Aujeszky’s disease virus, the expression profiles of the host and viral miRNAs have also been determined by ion sequencing (Sun et al., Reference Sun, Chen and Guan2019).
Electrochemical sensing
Amperometric and potentiometric, voltammetric, impedimetric, conductometric and field effect transistor-based biosensors are all examples of electrochemical sensing (Shirjang et al., Reference Shirjang, Mansoori, Asghari, Duijf, Mohammadi, Gjerstorff and Baradaran2019; Kozomara et al., Reference Kozomara, Birgaoanu and Griffiths-Jones2019). Amperometry-based sensors measure the current at a fixed applied voltage to identify analytes. Voltametric measurements, in contrast, take the current into account as the potential is raised at a specific rate. Li et al. (Reference Li, Li, Chen, Yue, Fan, Dong and Wang2023) developed method of sensing nucleic acids with a silicon nanowire field effect transistor biosensor and discovered miRNA in animal cells using this method.
Loop-mediated isothermal amplification (LAMP)
Compared to PCR, the advantage of LAMP procedures is that they can be carried out without the necessity for exact temperature cycling control (Jia et al., Reference Jia, Cong, Li, Yang, Sun, Parvizi and Zhao2012). The method is effective in identifying short RNA sequences like miRNAs (Peng et al., Reference Peng, Guo, Lu, Yue, Li, Jin and Yang2020). Multi-miRNAs can be detected using nano-biosensors consisting of graphene oxide and a dye that binds to DN (Wen et al., Reference Wen, Liang, Pan, Li, Zhang, Zhu and Long2020).
CRISPR-Cas aided sensor devices
On the basis of CRISPR-Cas (Clustered regularly interspaced short palindromic repeats) high specificity of binding and signal amplification capabilities, have demonstrated remarkable potential and drawn significant interest in site-specific DNA methylation detection (Yu et al., Reference Yu, Cao, He and Zhang2023).
Single-cell DNA methylome sequencing
Describe dynamic methylation events in incredibly varied cell populations. Although the experimental throughput and genomic coverage have grown, this method has low yields and large implementation costs (Wei and Wu, Reference Wei and Wu2022).
COBRA, or combined bisulfite restriction analysis
Unmethylated cytosine residues are differently converted to uracil using sodium bisulfite chemistry, whereas unaltered methylated cytosines are left. This is a standard method for evaluating DNA methylation. Then, utilizing particular downstream nucleic acid analysis techniques like PCR, qPCR and sequencing, methylated cytosines can be identified (Kumar et al., Reference Kumar, Chaudhary, Singh, Sukhija, Panwar, Saravanan and Panigrahi2020).
DNase I Seq
Digital DNase and DNase Seq are two techniques for producing short DNA strands from nuclear-accessible genomic regions through nuclease digestion. Next-generation sequencing is used to identify and analyse these small DNA strands, providing complete sequence details on the genomic segments that are accessible for nuclease digestion (Kumar et al., Reference Kumar, Chaudhary, Singh, Sukhija, Panwar, Saravanan and Panigrahi2020).
The application of EWAS (epigenome-wide association study) for identifying the epigenetic biomarkers linked to livestock health and productivity traits was severely constrained by the absence of commercially available epigenome analysis assays. Before using epigenetic biomarkers in livestock breeding and production management, epigenome-wide arrays for identifying epigenetic patterns in large samples must be developed. As a result, there is an urgent requirement to create assays tailored specifically for livestock that are based on epigenetic mechanisms (particularly DNA methylation) that are both highly reliable and readily available in the market.
Fanzor
The ‘Fanzor’ protein was discovered to be a eukaryotic programmable RNA-guided endonuclease that modifies human cells more precisely in an attempt to find a eukaryotic equivalent of CRISPR (Fadul et al., Reference Fadul, Arshad and Mehmood2023). Fanzor proteins (and prokaryotic TnpBs) regulate transposable element activity, presumably through methyltransferase activity. TnpB homologs exist in two different forms in eukaryotes: Fanzor1s and Fanzor2s. Fanzor1s and Fanzor2s originate from a single lineage of IS607 TnpBs with an unusual active site configuration, according to the evolutionary links between bacterial TnpBs and eukaryotic Fanzors (Yoon et al., Reference Yoon, Skopintsev, Shi, Chen, Adler, Al-Shimary and Doudna2023). TnpB has been linked to a novel class of RNA-guided systems known as OMEGA (Obligate Mobile Element-guided Activity) in recent reports. OMEGA systems comprise a non-coding RNA (ncRNA) transcribed from the transposon end region (called ωRNA) and an RNA-guided endonuclease protein. CRISPR-Cas systems descended from OMEGA systems, and TnpB gave rise to the single RNA-guided endonuclease Cas12 (Saito et al., Reference Saito, Xu, Faure, Maguire, Kannan, Altae-Tran and Zhang2023).
Conclusion
Exploring the integration of epigenetic information into breeding programmes offers promise for enhancing desired traits, with strategies including identifying epigenetic markers, conducting epigenome-wide association studies and employing epigenetic editing. However, challenges such as ethical considerations, environmental influences and technical hurdles must be addressed. Ensuring responsible use, understanding heritability, navigating regulatory frameworks and integrating epigenetic data with genomic information are crucial for successful implementation. Collaborative efforts are essential for realizing the potential of epigenetics in breeding while directing these complexities.
Author contributions
Pushpa and Ankit Magotra contributed equally in conceptualizing and writing the manuscript, Vikas Sindhu and Pradeep Chaudhary contributed in manuscript writing.
Funding
Not applicable.
Competing interests
Authors declared that there is no conflict of interest.
Ethical standards
This article does not contain any studies with human participants performed by any of the authors.
