Role of Circular RNAs in Cattle Health

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1		Maria-Anna Kyrgiafini	--	2174	2024-03-10 22:17:15	\|
2	Reference format revised.	Lindsay Dong	Meta information modification	2174	2024-03-11 03:11:34	\|

This entry is adapted from the peer-reviewed paper 10.3390/ani14050733

Circular RNAs (circRNAs) are derived from regions that are transcribed but do not code for proteins. Instead, they form covalent closed-loop structures and play a crucial role in many biological processes. Studies show that they have an important role in cattle health, welfare and productive characteristics.

noncoding RNAs (ncRNAs) livestock biomarkers cattle circRNA welfare

1. Introduction

The significance of livestock is paramount in the agricultural sector, both economically and as a key source of dietary protein. Livestock value chains are estimated to employ over 1.3 billion people globally, contributing to around 40% of the total agricultural production value ^[1]. Furthermore, in Europe, animal protein accounts for over 50% of the total protein consumption ^[2]. Notably, cattle, goats, and sheep are vital within this sector. Specifically, cattle play a significant role in milk and meat production, while goats and sheep, known for their adaptability, are particularly valuable in diverse environments and can thrive on marginal lands unsuitable for plant crops ^[3]. According to studies, 360 million cattle and 600 million small ruminants contribute 25% of the world’s animal products from such marginal lands ^[4]. Therefore, these livestock species are not only economically important but also provide essential nutrition and hold cultural value for rural communities.

However, in recent years, the livestock sector has encountered significant challenges and transformations. Climate change has led to extreme weather conditions like high temperatures, floods, and droughts, complicating agricultural production and reducing animal productivity ^[5]. Concurrently, the growing human population has escalated food demand, necessitating higher productivity ^[6]. This intensification of production heightens the risk of infectious diseases spreading ^[7]. Additionally, there is increased consumer concern regarding animal-rearing practices and the ethical procurement of animal-derived food products, underscoring the need for vigilant monitoring of animal welfare ^[8]. Given these challenges and the push towards more sustainable food systems, it is crucial to understand the molecular mechanisms underlying key physiological processes, such as animal disease resistance, environmental adaptation, etc. Developing biomarkers to monitor animal health and welfare and selecting suitable candidates for breeding programs are pivotal steps in this context, too.

Advancements in high-throughput sequencing, alongside progress in molecular biology and genetics, have brought noncoding RNAs (ncRNAs) into the spotlight. Noncoding RNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as key players in the regulation of various cellular processes with broader implications in the regulation of animals’ health, welfare, and production ^[9]^[10]^[11]. Additionally, due to their distinctive properties, many of these molecules have the potential to be used as biomarkers for various disorders and health conditions ^[8]^[12]^[13].

Compared to other ncRNAs, circRNAs remain less studied, with research focusing on their roles in livestock production, health, and welfare being still in its infancy. CircRNAs are distinctive, single-stranded RNA transcripts that form a covalently closed, continuous loop. Typically, precursor mRNAs (pre-mRNAs) are synthesized by RNA polymerase II (Pol II). This process is followed by canonical splicing, as introns are removed and exons are joined to form a linear RNA transcript (mature messenger RNA, mRNA) with a 5′–3′ polarity. However, an alternative splicing mechanism, termed “back-splicing”, can also occur. During back-splicing, the 3′ end of an exon is connected to the 5′ end of the same or an upstream exon, forming a 3′,5′-phosphodiester bond. This results in a unique closed-loop structure with a back-splicing junction site, a hallmark of circRNAs ^[14]^[15]^[16]. Furthermore, circRNAs can be classified into three primary types based on their origin: exon-derived circRNA (ecRNA), intron-derived circRNA (ciRNA), and exon-intron circRNA (EIcircRNA) ^[17]. Finally, circRNAs are noted for their high cellular stability, evolutionary conservation across species, and resistance to degradation by certain RNA-degrading enzymes ^[18]^[19]^[20].

2. Circular RNAs in Cattle

Cattle (Bos taurus) play a pivotal role in global agriculture, functioning as key economic keystones and nutritional reservoirs with far-reaching significance. As integral contributors to the meat and dairy industries, cattle have great economic importance. The mandate to optimize their productivity, health, and welfare converges at the intersection of economic sustainability and scientific progress, particularly in light of the many challenges faced by cattle farming, encompassing disease susceptibility ^[21], productivity oscillations, and environmental stressors ^[22]^[23]. The study of circRNAs can provide a better understanding of the intricate molecular mechanisms governing cattle physiology, presenting avenues for targeted interventions and innovative strategies to address the multifaceted challenges encountered by the cattle farming industry.

2.1. Milk Production

Lactation represents a dynamic physiological process essential for milk production, delivering crucial nutrition and immune benefits to the offspring while concurrently meeting the maintenance requirements of the mother ^[24]. In the context of dairy farming, milk serves as the primary product marketed for human consumption, with cattle contributing to 81% of the total global milk production ^[25]. Rich in biologically active fatty acids, including saturated fatty acids and conjugated linoleic acid, milk composition not only profoundly affects its flavor and nutritional profile but is also a key consideration in the breeding of dairy cattle, directly influencing the quality of fresh milk ^[26]. Numerous studies delve into the intricate interplay of circRNAs in milk fat metabolism and the lactation process, providing valuable insights that can serve as a roadmap for enhancing overall milk quality.

One of the pioneering studies in exploring the impact of circRNAs on lactation was conducted by Zhang et al. (2016) ^[27], who investigated the circRNA profiles in cow mammary glands at 90 and 250 days after giving birth. Notably, 80 circRNAs were identified to originate from all four casein-coding genes (CSN1S1, CSN1S2, CSN2, and CSN3). These circRNAs exhibited high expression levels in the mammary tissue of cows after 90 days of lactation, and they were found to contain multiple binding sites for the microRNA miR-2284 family. This suggests the active involvement of circRNAs in modulating the expression of the casein genes during lactation.

Furthermore, in a study led by Chen et al. (2021) ^[28], mammary gland tissues from three cows were analyzed during dry and peak lactation phases. Through high-throughput sequencing, the research revealed a significant reduction in miR-128 expression attributed to circ11103. Circ11103, highly present in mammary gland tissue, is key in regulating milk fat metabolism by enhancing the production of triglycerides and fatty acids through its interactions with miR-128. This miRNA, in turn, targets and suppresses the PPARGC1A gene, which is vital for milk fat metabolism, therefore affecting its function. Consequently, it is hypothesized that the circ11103/miR-128/PPARGC1A pathway exerts a regulatory effect on milk fat metabolism and fatty acid synthesis in dairy cows.

Similarly, in a study conducted by Liang et al. (2022) ^[29], the investigation into circRNAs in Holstein cow mammary tissues during early lactation compared to non-lactation was undertaken. Through high-throughput RNA sequencing (RNA-seq), 87 circRNAs were found to be significantly differentially expressed (DE) in peak lactation cows compared to non-lactating ones, with 68 being upregulated and 19 downregulated. These identified circRNAs are speculated to be intricately involved in diverse physiological processes, including fatty acid transport, triglyceride synthesis, as well as inflammation, and immune regulation ^[29].

Regarding specifically milk fat metabolism, Feng et al. (2022) ^[30] analyzed circRNA profiles in bovine mammary epithelial cells (BMECs) of cows with a high percentage of milk fat (HMF) and a low percentage of milk fat (LMF) to discern circRNAs associated with milk fat metabolism. The study unveiled a total of 290 DE circRNAs, comprising 142 upregulated and 148 downregulated ones. The host genes of these differentially expressed circRNAs were primarily linked to lipid metabolism, with the most enriched term being cholesterol transport. Among the enriched pathways, the PI3K-Akt signaling pathway took precedence, followed by ECM-receptor interaction and endocytosis, while other involved pathways included mTOR and AMPK. Following the construction of competitive endogenous RNA (ceRNA) networks, the researchers identified four regulatory networks (circ0001122/miR-12043/LIPG, circ0007367/miR-331-3p/CIDEA and PML, and circ0018269/miR-11989/RORC and HPX), underscoring their pivotal roles in regulating milk lipid metabolism ^[30]

2.2. Muscle Growth and Development

Meat constitutes a crucial component of the human diet and has significant implications for both health and the global economy ^[31]. Cattle meat consumption has demonstrated a consistent and stable trend over time ^[32]. In the realm of beef production, the intricate relationship between muscle growth in cattle and meat quality is paramount, influencing taste, tenderness, and overall desirability. Factors such as muscle fiber composition, intramuscular fat content, and connective tissue collectively contribute to the sensory attributes that define beef ^[33]. However, despite the fundamental role of circRNAs in gene regulation and cellular processes, only a limited body of research has explored their specific involvement in muscle growth and development in cattle.

Wei et al. (2017) ^[34] investigated the role of circRNAs in the muscle development of cattle by comparing embryonic and adult muscle samples from Chinese Qinchuan cattle, which are known for their superior meat quality. Their analysis revealed 828 DE circRNAs. Among these, circLMO7 emerged as one of the most downregulated circRNAs in adult muscle tissue compared to embryonic muscle tissue. The study focused on circLMO7 and demonstrated that, by functioning as a ceRNA for miR-378a-3p, circLMO7 positively regulates the expression of crucial target genes involved in myoblast differentiation and survival. These findings highlight the significant regulatory role of circLMO7 and circRNAs, in general, in the intricate molecular processes that govern myoblast biology.

The circRNAs associated with milk production and muscle growth and development according to the above studies are presented in Figure 1. It should be noted that the list is limited to circRNAs validated through molecular approaches, such as quantitative polymerase chain reaction (qPCR).

Figure 1. Overview of circRNAs associated with milk production and muscle growth and development in cattle.

2.3. Immunity

Immunity in cattle is a pivotal factor with profound implications for both animal health and the overall productivity of the livestock industry. A well-balanced and responsive immune system is critical, playing a key role not only in preventing and combatting infections but also in supporting overall health and performance ^[35]. Furthermore, there is a growing need to study immunity, particularly since the intensification of milk and beef production inevitably increases the risk of infectious disease spread and exacerbation ^[36]. Despite the acknowledged significance of immunity in cattle, the exploration of circRNAs in the context of bovine immunity is still in its early stages. The only available study associated with circRNAs and immunity in cattle focused on mastitis, a substantial economic burden and a significant challenge for the dairy industry.

More specifically, in the study by Bai et al. (2022) ^[37], the expression of circRNAs in Staphylococcus aureus-induced mastitis was explored using mammary tissue samples from healthy (HCN) and affected Holstein cows (HCU). Employing RNA-seq, 19 DE circRNAs were identified, with 6 upregulated and 13 downregulated in HCU compared to HCN. Notably, three circRNAs—circRNA2860, circRNA5323, and circRNA4027—showed consistent differential expression in both RNA-seq and qPCR analyses, suggesting their potential as key regulators in mastitis. Importantly, the host genes of these circRNAs, including TRPS1, SLC12A2, and MYH11, may play a direct or indirect role in the development of cow mastitis. Furthermore, DE circRNAs were significantly enriched in RNA polymerase transcription factor binding and the tight junction pathway, processes, and pathways particularly relevant to cow mammary epithelial tissue.

2.4. Heat Stress

In recent years, the impacts of global warming have become increasingly evident across various sectors, including the dairy industry. Heat stress (HS) significantly affects dairy cows, resulting in substantial economic losses for the industry annually. HS induces a range of physiological responses and ailments across diverse bodily systems when bovine species experience temperatures exceeding their intrinsic thermoregulatory thresholds. The subsequent chain of consequences includes a noticeable decline in reproductive efficiency, accompanied by a sharp deterioration in overall physiological well-being. This encompasses the onset of diseases, a decrease in reproductive capabilities, a reduction in milk production, and a concurrent decline in the qualitative attributes of the produced milk ^[38]^[39]^[40]. Therefore, recognizing the imperative to address the adverse impacts of heat stress, numerous studies are exploring the involvement of circRNAs in cattle subjected to heat stress.

Zhang et al. (2023) ^[41] conducted a comprehensive investigation into the impact of heat stress on key biological processes and the potential involvement of circRNAs in the heat stress response. Their study focused on discerning circRNA expression profiles in peripheral blood samples of cows during heat stress, revealing significant alterations. Specifically, the DE circRNAs were found to be associated with five primary signaling pathways: choline metabolism, the PI3K/AKT signaling pathway, the HIF-1 signaling pathway, the longevity-regulating pathway, and autophagy. Moreover, the study pinpointed three specific circRNAs (ciRNA1282, circRNA4205, circRNA12923) as crucial components in the heat stress response. These circRNAs were notable for their enrichment in multiple pathways and their identification as binding to multiple miRNAs.

Another compelling study, conducted by Zeng et al. (2023) ^[42], delved into the association between circRNAs and hormonal changes within the hypothalamic-pituitary-mammary gland (HPM) axis. The comprehensive analysis spanned various tissues, including blood samples, as well as the hypothalamus, pituitary, and mammary gland tissues. The investigation uncovered distinctive expression profiles of circRNAs in these tissues, with 1680, 1112, and 521 DE circRNAs identified in the hypothalamus, pituitary, and mammary gland, respectively. Significantly, a notable proportion of these circRNAs exhibited upregulation, with 1111, 2461, and 250 circRNAs displaying increased expression, while 569, 1112, and 271 showed downregulation in their respective tissues.

As previously mentioned, the circRNAs associated with heat stress and immunity in the above studies are presented in Figure 2. The list is limited to circRNAs validated through molecular approaches.

Figure 2. Overview of circRNAs associated with heat stress and immunity in cattle.

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