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This report is written by MaltSci based on the latest literature and research findings

What is the role of non-coding RNA in gene regulation? ​

Abstract ​

Non-coding RNAs (ncRNAs) have emerged as crucial regulators of gene expression, playing significant roles in various biological processes and disease mechanisms. Unlike protein-coding RNAs, ncRNAs do not translate into proteins; instead, they function at multiple levels of gene regulation, including transcriptional, post-transcriptional, and epigenetic modifications. Dysregulation of ncRNA expression has been linked to numerous pathological conditions, including cancer, cardiovascular diseases, and neurological disorders. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are particularly prominent in these contexts, influencing processes such as cell proliferation, apoptosis, and differentiation. The biogenesis of ncRNAs involves complex pathways that contribute to their functional diversity. This review provides a comprehensive overview of the classification, biogenesis, and mechanisms of action of ncRNAs in gene regulation. It highlights their essential roles in cellular processes and their implications in health and disease, paving the way for future research endeavors that may harness ncRNAs for therapeutic applications. Understanding these regulatory networks is vital for developing innovative strategies to target ncRNAs in disease treatment, ultimately improving patient outcomes.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Overview of Non-coding RNAs
    • 2.1 Classification of Non-coding RNAs
    • 2.2 Biogenesis of Non-coding RNAs
  • 3 Mechanisms of Gene Regulation by Non-coding RNAs
    • 3.1 Transcriptional Regulation
    • 3.2 Post-transcriptional Regulation
    • 3.3 Epigenetic Modifications
  • 4 Functional Roles of Non-coding RNAs in Cellular Processes
    • 4.1 Development and Differentiation
    • 4.2 Cell Cycle and Apoptosis
    • 4.3 Stress Responses
  • 5 Non-coding RNAs in Disease Mechanisms
    • 5.1 Non-coding RNAs in Cancer
    • 5.2 Non-coding RNAs in Cardiovascular Diseases
    • 5.3 Non-coding RNAs in Neurological Disorders
  • 6 Future Directions and Therapeutic Implications
    • 6.1 Potential for ncRNA-based Therapies
    • 6.2 Challenges in ncRNA Research
  • 7 Conclusion

1 Introduction ​

Non-coding RNAs (ncRNAs) have gained significant attention in recent years due to their crucial roles in the regulation of gene expression and their involvement in various biological processes and disease mechanisms. Unlike their protein-coding counterparts, ncRNAs do not translate into proteins; instead, they function at multiple levels of gene regulation, including transcriptional, post-transcriptional, and epigenetic modifications. This has led to a paradigm shift in our understanding of gene regulation, emphasizing the importance of RNA molecules beyond their traditional roles in protein synthesis [1].

The significance of ncRNAs extends to their implications in health and disease. Dysregulation of ncRNA expression has been linked to a wide range of pathological conditions, including cancer, cardiovascular diseases, and neurological disorders [2][3]. For instance, microRNAs (miRNAs), a prominent class of ncRNAs, have been identified as key regulators in oncogenesis, influencing processes such as cell proliferation, apoptosis, and metastasis [4]. Long non-coding RNAs (lncRNAs) have also emerged as critical players in the modulation of gene expression, affecting cellular processes such as differentiation and response to stress [5]. Moreover, recent advances in high-throughput sequencing technologies and bioinformatics have significantly enhanced our ability to identify and characterize ncRNAs, unveiling their complex interactions within regulatory networks [6].

Current research has revealed diverse classifications of ncRNAs, including miRNAs, lncRNAs, circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs), each with distinct biogenesis pathways and functional roles [7]. The understanding of these classifications is vital, as it lays the groundwork for exploring their specific mechanisms of action in gene regulation. For example, miRNAs are known to bind to target mRNAs, leading to their degradation or translational repression, while lncRNAs can modulate transcription by interacting with chromatin and transcription factors [8][9].

This review is organized to provide a comprehensive overview of the multifaceted roles of ncRNAs in gene regulation. Following this introduction, we will first explore the classification and biogenesis of ncRNAs, highlighting the mechanisms through which they are synthesized and processed. Subsequently, we will delve into the various mechanisms by which ncRNAs regulate gene expression, including transcriptional control, post-transcriptional modifications, and epigenetic changes. The functional roles of ncRNAs in critical cellular processes, such as development, differentiation, and responses to stress, will be examined in detail. We will also discuss the involvement of ncRNAs in disease mechanisms, particularly in cancer, cardiovascular diseases, and neurological disorders. Finally, we will outline future research directions and potential therapeutic implications of ncRNAs, emphasizing their promise as novel targets for therapeutic interventions.

By synthesizing current knowledge on the diverse functions of ncRNAs, this review aims to elucidate their essential roles in gene regulation and their implications in health and disease, paving the way for future research endeavors that may harness ncRNAs for therapeutic applications.

2 Overview of Non-coding RNAs ​

2.1 Classification of Non-coding RNAs ​

Non-coding RNAs (ncRNAs) play a pivotal role in the regulation of gene expression, serving as crucial regulators of various biological processes. These RNA molecules do not encode proteins but are involved in diverse regulatory mechanisms that influence cellular functions and contribute to the pathophysiology of numerous diseases, including cancer.

Overview of Non-coding RNAs ​

Non-coding RNAs can be broadly classified into several categories based on their length and function. The primary types include:

  1. MicroRNAs (miRNAs): Small, approximately 18-24 nucleotides in length, miRNAs regulate gene expression at the post-transcriptional level by binding to complementary sequences on target mRNAs, leading to mRNA degradation or inhibition of translation. They are known to influence over 30% of protein-coding genes and play critical roles in cellular processes such as differentiation, proliferation, and apoptosis[10].

  2. Long Non-coding RNAs (lncRNAs): These are longer than 200 nucleotides and have been shown to regulate gene expression through various mechanisms, including chromatin remodeling, transcriptional regulation, and interaction with other RNA molecules. LncRNAs can function as scaffolds for protein complexes, guide chromatin-modifying enzymes to specific genomic locations, and even act as decoys for miRNAs[5].

  3. Circular RNAs (circRNAs): These are a class of ncRNAs characterized by their covalently closed loop structure. CircRNAs can function as miRNA sponges, regulating the availability of miRNAs to their target mRNAs, thus influencing gene expression indirectly[11].

Classification of Non-coding RNAs ​

Non-coding RNAs can be classified based on their size, structure, and functional roles:

  1. Small Non-coding RNAs: This group includes miRNAs and small interfering RNAs (siRNAs). They typically range from 20 to 30 nucleotides in length and are primarily involved in post-transcriptional regulation of gene expression.

  2. Long Non-coding RNAs: As previously mentioned, lncRNAs exceed 200 nucleotides and can have diverse roles in gene regulation, including acting as transcriptional regulators and influencing chromatin structure[12].

  3. Ribosomal RNAs (rRNAs) and Transfer RNAs (tRNAs): While primarily involved in protein synthesis, rRNAs and tRNAs are also considered non-coding RNAs and contribute to the overall regulation of gene expression.

  4. Circular RNAs: This novel class of ncRNAs has garnered attention for its role in gene regulation, particularly as miRNA sponges, which can modulate the activity of miRNAs and thus influence the expression of target genes[7].

  5. Other Regulatory RNAs: This category encompasses various types of non-coding RNAs that may have regulatory roles, including those involved in RNA processing and modification, as well as regulatory elements found in the non-coding regions of the genome.

In summary, non-coding RNAs represent a vast and diverse group of molecules that play essential roles in gene regulation. Their ability to modulate gene expression through various mechanisms underscores their significance in maintaining cellular homeostasis and their potential as therapeutic targets in diseases, including cancer and cardiovascular conditions[2][3].

2.2 Biogenesis of Non-coding RNAs ​

Non-coding RNAs (ncRNAs) play crucial roles in gene regulation and are integral to various biological processes. They are defined as RNA molecules that do not encode proteins but have significant regulatory functions in gene expression and cellular activities. The biogenesis of non-coding RNAs involves several key mechanisms and processes, leading to their diverse functional roles in the cell.

Non-coding RNAs are broadly categorized into several types, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). These molecules are involved in the regulation of gene expression at multiple levels, including transcriptional and post-transcriptional regulation. For instance, microRNAs are known to regulate gene expression by binding to complementary sequences on target mRNAs, leading to their degradation or translational repression, thereby influencing various physiological and pathological processes, including cancer development and progression [2].

The biogenesis of non-coding RNAs typically begins with the transcription of their respective genes by RNA polymerases. For example, miRNAs are transcribed as long primary transcripts (pri-miRNAs) that are processed by the enzyme Drosha into precursor miRNAs (pre-miRNAs) in the nucleus. These pre-miRNAs are then exported to the cytoplasm, where they are further processed by Dicer into mature miRNAs [13]. Similarly, lncRNAs are transcribed from the genome and can undergo various processing events, including splicing and modifications, to achieve their functional forms [5].

Non-coding RNAs also participate in epigenetic regulation, which refers to heritable changes in gene expression that do not involve alterations to the underlying DNA sequence. They can influence chromatin structure and gene expression by interacting with chromatin-modifying complexes and transcription factors [8]. For instance, lncRNAs have been shown to recruit chromatin-modifying enzymes to specific genomic loci, thereby regulating the transcription of nearby genes [3].

Moreover, non-coding RNAs are implicated in various cellular processes such as cell proliferation, differentiation, and apoptosis. They can modulate signaling pathways and contribute to cellular responses to stress, thereby playing vital roles in maintaining cellular homeostasis [7]. In the context of disease, dysregulation of non-coding RNAs has been associated with various conditions, including cancer, cardiovascular diseases, and neurodegenerative disorders [14].

The interaction of non-coding RNAs with other cellular molecules, such as proteins and other RNAs, is essential for their regulatory functions. For example, circRNAs can act as sponges for miRNAs, thereby sequestering them and preventing them from binding to their target mRNAs, which can alter gene expression profiles [11].

In summary, non-coding RNAs are critical regulators of gene expression, influencing various biological processes through their intricate biogenesis and multifaceted mechanisms of action. They represent a significant area of research with potential therapeutic implications, particularly in understanding and treating diseases associated with their dysregulation.

3 Mechanisms of Gene Regulation by Non-coding RNAs ​

3.1 Transcriptional Regulation ​

Non-coding RNAs (ncRNAs) play a pivotal role in the regulation of gene expression, particularly through mechanisms of transcriptional regulation. These RNA molecules, which do not encode proteins, have emerged as significant regulators of various cellular processes, including gene transcription, chromatin remodeling, and epigenetic modifications.

One of the primary functions of ncRNAs, especially long non-coding RNAs (lncRNAs), is to interact with chromatin and transcriptional machinery, thereby influencing gene expression. For instance, lncRNAs can guide chromatin remodeling factors to specific genomic loci, leading to changes in chromatin architecture that either promote or inhibit transcription. This interaction can result in the induction of chromosomal looping, which facilitates the physical proximity of enhancers and promoters, thus enhancing transcriptional activity [15].

Moreover, ncRNAs are involved in the epigenetic regulation of gene expression. They can direct the deposition of epigenetic modifications such as histone modifications and DNA methylation, which are crucial for the maintenance of gene silencing or activation states. This role of ncRNAs in epigenetic regulation highlights their capacity to influence not only immediate transcriptional outcomes but also the long-term stability of gene expression patterns [5].

Additionally, ncRNAs can function in a transcriptional regulatory capacity by affecting the transcriptional cycle itself. For example, studies have shown that certain lncRNAs can bind to RNA polymerase II and alter its activity, thereby modulating the transcriptional elongation process. This suggests that ncRNAs are not merely by-products of transcription but active participants in regulating the transcriptional landscape [16].

In the context of disease, particularly cancer, the dysregulation of ncRNAs can lead to aberrant gene expression profiles. Many lncRNAs have been identified as oncogenes or tumor suppressors, influencing pathways critical for cell proliferation and survival. Their regulatory roles can also extend to the modulation of cancer stem cell properties and epithelial-mesenchymal transition (EMT), which are vital for tumor progression and metastasis [2].

Furthermore, the interaction of ncRNAs with transcription factors (TFs) and other RNA-binding proteins can create complex regulatory networks. This interaction can influence the availability and activity of TFs, thereby affecting the transcription of target genes. For instance, lncRNAs can act as scaffolds that bring together multiple regulatory proteins, enhancing or inhibiting the transcriptional response to various stimuli [17].

In summary, non-coding RNAs are crucial regulators of gene expression through various transcriptional mechanisms. Their ability to interact with chromatin, modulate transcriptional machinery, and influence epigenetic states underscores their significance in both normal physiology and pathological conditions. As research continues to unveil the complexities of ncRNA functions, their potential as therapeutic targets and biomarkers in diseases, particularly cancer, becomes increasingly evident [5][15][17].

3.2 Post-transcriptional Regulation ​

Non-coding RNAs (ncRNAs) play a pivotal role in the post-transcriptional regulation of gene expression, influencing various cellular processes and contributing to the complexity of gene regulatory networks. This regulation occurs through multiple mechanisms, predominantly involving microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and other small RNA classes.

MiRNAs are small ncRNAs that primarily function by binding to the 3' untranslated regions (3' UTR) of target mRNAs, leading to their degradation or translational repression. This canonical mode of action allows miRNAs to modulate the expression of a significant number of genes, thereby impacting processes such as development, metabolism, and disease progression. For instance, miRNAs have been implicated in the regulation of key pathogenic mechanisms in diabetic kidney disease, where specific miRNAs can either exacerbate or mitigate renal injury [18].

In addition to miRNAs, lncRNAs also play crucial roles in post-transcriptional regulation. They can function as endogenous competitive RNAs that sequester miRNAs, thereby preventing miRNAs from binding to their target mRNAs and allowing for the derepression of these targets. LncRNAs are known to regulate gene expression at various levels, including transcriptional, post-transcriptional, and epigenetic levels [19]. They are involved in processes such as gene splicing, mRNA stability, and protein stability, thus influencing the overall gene expression landscape [20].

The regulatory functions of ncRNAs extend beyond mere repression or activation of target genes. They can also be involved in the coordination of transcriptional and post-transcriptional regulatory mechanisms, creating a complex regulatory network. For example, emerging evidence suggests that miRNAs can also influence gene transcription directly, thereby expanding their regulatory roles beyond post-transcriptional repression [21].

Moreover, the interplay between different classes of ncRNAs contributes to the robustness of gene regulatory networks. The integration of coding and non-coding transcripts forms intricate competing endogenous RNA (ceRNA) networks, where various RNA species can compete for shared miRNA pools. Dysregulation of these networks has been linked to various diseases, including cancer [22].

The discovery of non-coding RNAs has reshaped our understanding of gene regulation, highlighting their importance in maintaining genomic stability and regulating gene expression. Their involvement in both physiological and pathological processes underscores the necessity of further research to elucidate the specific mechanisms through which ncRNAs exert their effects [15].

In summary, non-coding RNAs are essential regulators of gene expression, primarily through post-transcriptional mechanisms involving miRNAs and lncRNAs. They influence a wide array of biological processes by modulating mRNA stability, translational efficiency, and transcriptional activity, thereby playing critical roles in cellular function and organismal development.

3.3 Epigenetic Modifications ​

Non-coding RNAs (ncRNAs) play a significant role in the regulation of gene expression, particularly through epigenetic modifications. Epigenetics refers to heritable changes in gene expression that do not involve alterations to the underlying DNA sequence. Non-coding RNAs are pivotal in this regulatory landscape, influencing various cellular processes, including growth, differentiation, and disease progression.

One of the primary mechanisms through which ncRNAs exert their effects is by guiding epigenetic modifications. These modifications can occur on DNA or histone proteins, which ultimately affect gene transcription. For instance, microRNAs (miRNAs) are a class of ncRNAs that can regulate the expression of numerous genes post-transcriptionally by binding to complementary sequences in the 3' untranslated region (UTR) of mRNA transcripts. This interaction can lead to mRNA degradation or translational repression, effectively silencing gene expression [23].

Furthermore, ncRNAs are involved in the regulation of chromatin structure, which is crucial for transcriptional control. Long non-coding RNAs (lncRNAs) and natural antisense transcripts (NATs) can modulate chromatin states by recruiting epigenetic modifiers that add or remove chemical groups on histones or DNA, thereby influencing gene accessibility. For example, lncRNAs can interact with chromatin remodeling complexes to either promote or inhibit transcription depending on the specific context and targets involved [24].

Recent studies have also highlighted the interplay between ncRNAs and other epigenetic regulators. For instance, it has been shown that epigenetic modifications can silence miRNA coding genes, while miRNAs can act as effectors of transcriptional gene silencing, targeting genes that encode epigenetic modifiers. This reciprocal relationship indicates a complex regulatory network where ncRNAs both influence and are influenced by epigenetic changes [23][25].

Moreover, the role of ncRNAs in the context of cancer has garnered significant attention. Alterations in ncRNA expression and function can lead to disruptions in epigenetic regulation, contributing to cancer initiation and progression. For example, the inactivation of miRNA genes by epimutations has been observed in gliomas, illustrating the critical impact of ncRNAs on the epigenetic landscape in malignancies [26].

In summary, non-coding RNAs are integral to the regulation of gene expression through various epigenetic mechanisms. They not only modulate chromatin structure and gene accessibility but also interact with other epigenetic factors, creating a complex web of regulatory pathways that govern cellular function and contribute to disease processes. Understanding these mechanisms is essential for developing novel therapeutic strategies targeting epigenetic networks in various diseases, particularly cancer [27][28].

4 Functional Roles of Non-coding RNAs in Cellular Processes ​

4.1 Development and Differentiation ​

Non-coding RNAs (ncRNAs) play a crucial role in the regulation of gene expression and are integral to various cellular processes, including development and differentiation. They are classified into different types, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and other regulatory RNAs, each contributing uniquely to cellular functions.

One of the primary functions of ncRNAs is their involvement in epigenetic regulation. Epigenetics refers to heritable changes in gene expression that do not involve alterations to the underlying DNA sequence. Research has demonstrated that ncRNAs are vital in regulating cell growth, differentiation, and responses to external stimuli, which is especially significant during developmental processes. For instance, lncRNAs have been recognized as key regulators in the specification of cellular identities by modulating gene expression programs through various mechanisms, including transcriptional and post-transcriptional regulation[29].

In the context of skin biology, advances in genome analyses have highlighted the critical roles of ncRNAs in epidermal development and keratinocyte differentiation. These molecules can integrate multiple external signals and modulate nuclear responses, thereby influencing transcriptional programs essential for normal skin development and maintenance[30]. Moreover, ncRNAs have been implicated in the regulation of adult stem-cell maintenance in stratified epithelial tissues, indicating their importance in both normal physiology and in pathological conditions[30].

Specifically, lncRNAs have been shown to play significant roles in the differentiation of mammalian cells. They can influence various differentiation systems by modulating gene expression at multiple levels, thereby impacting cellular transitions during differentiation processes[29]. For example, studies have indicated that specific lncRNAs contribute to the control of mammalian cell differentiation, suggesting their involvement in developmental pathways and potential applications in regenerative medicine[29].

Additionally, the role of ncRNAs extends to drug resistance in cancer, where they regulate the expression of genes associated with drug resistance and influence pathways related to cell cycle regulation and apoptosis[2]. This highlights their dual role in both normal cellular differentiation and pathological states, such as cancer.

In summary, non-coding RNAs serve as pivotal regulators of gene expression, influencing developmental processes and cellular differentiation through complex regulatory networks. Their ability to integrate signals and modulate gene expression makes them essential for maintaining cellular identity and function, as well as for understanding the underlying mechanisms of various diseases.

4.2 Cell Cycle and Apoptosis ​

Non-coding RNAs (ncRNAs) play a pivotal role in the regulation of gene expression, influencing various cellular processes including the cell cycle and apoptosis. These regulatory molecules, which include long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), do not encode proteins but are crucial in modulating transcriptional and post-transcriptional events.

The mechanisms by which ncRNAs regulate gene expression are diverse. For instance, lncRNAs can interact with chromatin-modifying complexes to alter the transcriptional landscape of genes. They may also act as scaffolds, bringing together various proteins to form functional complexes that regulate gene activity [8]. Moreover, lncRNAs have been implicated in the regulation of apoptosis, where they influence the transcription of apoptotic genes, thus affecting the cell's decision to undergo programmed cell death [31].

MicroRNAs, another class of ncRNAs, primarily function by binding to complementary sequences in target mRNAs, leading to their degradation or inhibition of translation. This post-transcriptional regulation is critical in maintaining cellular homeostasis and has been shown to affect the cell cycle by modulating genes involved in cell proliferation and survival [2]. The dysregulation of miRNAs can lead to aberrant cell cycle progression and contribute to oncogenesis, as they can promote resistance to anticancer treatments by altering the expression of drug resistance-related genes [2].

CircRNAs, a relatively recent discovery in the ncRNA landscape, also play significant roles in gene regulation. They can function as miRNA sponges, sequestering miRNAs and preventing them from interacting with their target mRNAs, thereby influencing gene expression indirectly [32]. This ability to modulate the availability of miRNAs further underscores the complex regulatory network orchestrated by ncRNAs in cellular processes.

In the context of apoptosis, ncRNAs are essential in determining the fate of cells. They can modulate various apoptotic pathways, such as influencing the activity of caspases and other pro-apoptotic factors. For example, during apoptosis, certain lncRNAs have been found to regulate the expression of genes that encode proteins involved in the apoptotic machinery, thereby impacting the cell's response to apoptotic stimuli [33]. Furthermore, the interplay between ncRNAs and signaling pathways associated with apoptosis can lead to either the promotion or inhibition of cell death, depending on the cellular context and the specific ncRNAs involved [31].

In summary, non-coding RNAs are integral to the regulation of gene expression, significantly influencing cellular processes such as the cell cycle and apoptosis. Their multifaceted roles highlight their importance in maintaining cellular homeostasis and their potential as therapeutic targets in diseases such as cancer, where dysregulation of these pathways is often observed [34].

4.3 Stress Responses ​

Non-coding RNAs (ncRNAs) play critical roles in gene regulation and are increasingly recognized for their involvement in cellular processes, particularly in response to various stress conditions. They are classified into different categories, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), small interfering RNAs (siRNAs), and circular RNAs (circRNAs), each contributing uniquely to gene expression regulation.

One of the primary functions of ncRNAs is to modulate gene expression at multiple levels, including transcriptional, post-transcriptional, and translational stages. For instance, lncRNAs, which are longer than 200 nucleotides, have been shown to engage in various regulatory mechanisms such as chromatin remodeling, dosage compensation, and facilitating nuclear organization. They can influence the expression of target genes by acting as scaffolds, guides, or decoys, thereby impacting cellular identity and function during stress responses [35].

In the context of stress responses, ncRNAs are integral to the plant's ability to adapt to both abiotic and biotic stresses. For example, lncRNAs are involved in the regulation of stress memory, enabling plants to "remember" past stress events and respond more effectively to future challenges. This is achieved through epigenetic modifications, such as DNA methylation and histone modifications, which alter gene expression states and contribute to the inheritance of stress responses [36].

Moreover, small RNAs, including miRNAs and siRNAs, are crucial in silencing complementary mRNAs, thus regulating gene expression in response to environmental stresses. They can modulate the expression of genes involved in defense mechanisms, allowing plants to fine-tune their responses to pathogens and environmental fluctuations [37].

Recent studies highlight the extensive involvement of ncRNAs in plant stress signaling pathways, where they interact with various molecular components to orchestrate complex regulatory networks. For instance, lncRNAs have been identified as key players in integrating phytohormone signaling pathways, such as abscisic acid (ABA) and jasmonate (JA), which are vital for stress adaptation [38].

In summary, non-coding RNAs serve as essential regulators of gene expression, particularly in the context of stress responses. They facilitate the modulation of gene activity through diverse mechanisms, contributing to the plant's ability to adapt to changing environmental conditions. Understanding the functional roles of ncRNAs in stress responses not only provides insights into plant biology but also opens avenues for developing climate-resilient crops through targeted breeding strategies.

5 Non-coding RNAs in Disease Mechanisms ​

5.1 Non-coding RNAs in Cancer ​

Non-coding RNAs (ncRNAs) play a pivotal role in gene regulation, particularly in the context of cancer, by influencing various biological processes and contributing to disease mechanisms. NcRNAs encompass a diverse group of RNA molecules that do not code for proteins but are essential for regulating gene expression and cellular functions. Among the most studied types of ncRNAs are microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), both of which have been implicated in the regulation of gene networks and pathways relevant to cancer biology.

MiRNAs are short, approximately 22 nucleotides in length, and function primarily by binding to complementary sequences on target messenger RNAs (mRNAs), leading to translational repression or degradation of these mRNAs. This post-transcriptional regulation allows miRNAs to modulate the expression of multiple genes simultaneously, influencing processes such as cell proliferation, differentiation, and apoptosis. Altered expression of miRNAs has been associated with the initiation and progression of various malignancies, including lung, breast, and prostate cancers, highlighting their role as potential oncogenes or tumor suppressors [39].

LncRNAs, on the other hand, are longer RNA molecules that can regulate gene expression through several mechanisms, including chromatin remodeling, transcriptional regulation, and modulation of mRNA stability. They have been shown to interact with DNA, RNA, and proteins, thereby influencing various cellular processes. The dysregulation of lncRNAs is often observed in cancer and can contribute to tumorigenesis by affecting pathways related to cell cycle regulation, apoptosis, and epithelial-mesenchymal transition (EMT) [2]. For instance, lncRNAs can promote drug resistance by regulating genes involved in drug metabolism and transport, thereby impacting the effectiveness of cancer therapies [2].

Moreover, the interaction between ncRNAs and other cellular components, such as signaling pathways and epigenetic modifiers, further complicates their roles in cancer. For example, ncRNAs can influence the expression of genes involved in angiogenesis, a critical process for tumor growth and metastasis [40]. This regulation occurs through both transcriptional and post-transcriptional mechanisms, making ncRNAs crucial players in the tumor microenvironment and in the communication between tumor cells and surrounding stromal cells [41].

Recent studies have also highlighted the involvement of ncRNAs in the resistance mechanisms to anticancer drugs, where they can affect the expression of drug resistance-related genes and alter intracellular drug concentrations [2]. Additionally, the crosstalk between ncRNAs and RNA modifications, such as N6-methyladenosine (m6A), has been shown to play a significant role in cancer growth and progression [42].

In summary, non-coding RNAs serve as critical regulators of gene expression and play multifaceted roles in cancer biology. Their involvement in various mechanisms of tumorigenesis, drug resistance, and cellular communication underscores their potential as biomarkers and therapeutic targets in cancer treatment [39][43]. The continued exploration of ncRNAs may provide valuable insights into the complexities of cancer and lead to the development of innovative therapeutic strategies.

5.2 Non-coding RNAs in Cardiovascular Diseases ​

Non-coding RNAs (ncRNAs) play a crucial role in gene regulation, particularly in the context of cardiovascular diseases (CVDs). These RNA molecules, which do not encode proteins, are essential regulators of gene expression and are involved in various biological processes that can influence the pathogenesis of CVDs.

NcRNAs can be categorized into several types, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Each type has distinct mechanisms of action and implications for cardiovascular health. For instance, miRNAs are small RNA molecules that regulate gene expression at the post-transcriptional level by binding to target mRNAs, leading to their degradation or translational repression. This regulation is critical in processes such as cardiac development, hypertrophy, and response to stress, which are all pivotal in the progression of heart diseases [44].

Long non-coding RNAs (lncRNAs) are emerging as significant regulators of gene expression through various mechanisms, including epigenetic modifications, modulation of transcription, and acting as molecular sponges for miRNAs. They have been implicated in multiple aspects of cardiovascular biology, including cardiac hypertrophy, fibrosis, and ischemic injury [45]. Their dynamic expression in different cardiovascular conditions suggests they could serve as biomarkers and therapeutic targets for CVDs [46].

CircRNAs also contribute to cardiovascular disease mechanisms, primarily through their ability to function as miRNA sponges, thus regulating the availability of miRNAs to their target mRNAs. This interaction can influence the expression of genes involved in cardiovascular pathophysiology [11]. The circRNA-miRNA-mRNA axis has been highlighted as a significant regulatory network that plays a role in the evolution and development of CVDs [47].

Furthermore, the role of ncRNAs extends to age-related cardiovascular diseases, where they regulate processes such as oxidative stress and inflammation, which are known to exacerbate CVD risk [48]. The regulatory functions of ncRNAs in these contexts underscore their potential as therapeutic targets and biomarkers for diagnosing and monitoring cardiovascular conditions [49].

In summary, non-coding RNAs are integral to the regulation of gene expression in cardiovascular diseases, influencing a wide array of pathological processes. Their ability to modulate gene networks highlights their significance in both the understanding and treatment of cardiovascular disorders. As research progresses, the therapeutic potential of targeting ncRNAs offers promising avenues for innovative strategies in managing cardiovascular diseases.

5.3 Non-coding RNAs in Neurological Disorders ​

Non-coding RNAs (ncRNAs) play a crucial role in the regulation of gene expression and are increasingly recognized as significant players in the pathogenesis of various neurological disorders. These RNA molecules, which do not encode proteins, are involved in diverse cellular processes, including gene regulation, cellular signaling, and maintenance of neuronal function. The dysregulation of ncRNAs has been implicated in a range of neurological and neuropsychiatric conditions, highlighting their importance in both normal physiology and disease mechanisms.

MicroRNAs (miRNAs), a prominent class of ncRNAs, are involved in the regulation of gene expression at the post-transcriptional level. They can modulate the stability and translation of messenger RNAs (mRNAs) by binding to complementary sequences, leading to gene silencing. Evidence suggests that miRNAs play essential roles in various aspects of neural development, such as the proliferation of neural stem cells, neuronal differentiation, and synaptogenesis. Dysregulation of miRNAs has been linked to mental disorders and neurodegenerative diseases, indicating their critical function in maintaining neural homeostasis (Bian & Sun, 2011) [50].

Long non-coding RNAs (lncRNAs) are another class of ncRNAs that have been shown to regulate gene expression by interacting with chromatin, transcription factors, and other regulatory molecules. These lncRNAs can influence the expression of protein-coding genes, thereby affecting various cellular processes. In the context of neurological disorders, lncRNAs have been implicated in the regulation of neuroinflammation, apoptosis, and synaptic plasticity, all of which are vital for maintaining normal brain function. Their deregulation may contribute to the pathophysiology of conditions such as Alzheimer's disease and Parkinson's disease (Ruffo et al., 2023) [51].

Circular RNAs (circRNAs), another emerging class of ncRNAs, have also garnered attention for their regulatory roles. They can function as molecular sponges for miRNAs, thereby modulating the availability of miRNAs to target mRNAs. This mechanism of action has implications for understanding the regulatory networks involved in neurodegenerative diseases, where circRNAs may contribute to the dysregulation of gene expression (Tan et al., 2012) [52].

The complex interactions among various types of ncRNAs create intricate regulatory networks that can significantly impact neuronal health and disease. For instance, the dysregulation of ncRNAs has been linked to the progression of neurological disorders through mechanisms such as altered synaptic function, increased neuroinflammation, and disrupted neuronal survival pathways (Ilieva, 2024) [53].

Furthermore, the potential of ncRNAs as diagnostic and therapeutic targets in neurological disorders is an area of active research. Specific ncRNA signatures may serve as biomarkers for early disease detection, while manipulating ncRNA expression could open new avenues for innovative therapies aimed at restoring normal gene regulation in affected neuronal populations (Zakharova et al., 2025) [54].

In summary, non-coding RNAs are integral to the regulation of gene expression and play pivotal roles in the pathogenesis of neurological disorders. Their diverse functions and regulatory mechanisms underscore the importance of continued research into ncRNAs, which may ultimately lead to novel diagnostic and therapeutic strategies for these challenging conditions.

6 Future Directions and Therapeutic Implications ​

6.1 Potential for ncRNA-based Therapies ​

Non-coding RNAs (ncRNAs) play a crucial role in gene regulation, significantly influencing various biological processes, including development, cellular differentiation, and responses to environmental stimuli. They encompass a wide array of functional classes, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs, which collectively contribute to the regulation of gene expression at multiple levels, including transcriptional and post-transcriptional processes.

NcRNAs are integral to the modulation of gene expression networks, affecting key cellular functions such as proliferation, apoptosis, and immune responses. For instance, aberrant expression of ncRNAs has been linked to tumor progression, metastasis, and therapeutic responses in cancer, highlighting their potential as biomarkers and therapeutic targets [55]. Moreover, the interactions of ncRNAs with various cellular pathways, including MAPK, Wnt, and PI3K/AKT/mTOR, illustrate their extensive regulatory influence on gene expression [55].

The therapeutic implications of ncRNAs are increasingly recognized, particularly in the context of precision medicine. Their tissue-specific expression patterns present unique opportunities for targeted therapies, enabling the development of novel RNA-based therapeutics aimed at restoring normal gene expression [55]. Strategies under investigation include anti-microRNA therapies and microRNA mimics, which seek to counteract the effects of dysregulated ncRNAs in pathological conditions [55].

The potential for ncRNA-based therapies extends beyond cancer treatment. In cardiovascular diseases, for example, ncRNAs have been identified as critical regulators of gene expression and are emerging as therapeutic targets. The development of RNA interference (RNAi) drugs and other ncRNA-based interventions holds promise for treating conditions such as heart failure and atherosclerosis [56].

Despite the promising prospects, challenges remain in the therapeutic application of ncRNAs. Issues such as specificity, stability, and immune responses pose significant hurdles. Innovative approaches, including modified oligonucleotides and targeted delivery systems, are being developed to enhance the efficacy and safety of ncRNA-based therapies [55]. Furthermore, ongoing research aims to better understand the biogenesis and functional modulation of ncRNAs, which could pave the way for more effective therapeutic strategies [57].

In summary, non-coding RNAs are pivotal regulators of gene expression, with substantial implications for therapeutic development. As research progresses, the potential for ncRNA-based therapies to provide individualized and effective treatment options in various diseases continues to expand, ultimately improving patient outcomes and facilitating early diagnosis and monitoring opportunities [55].

6.2 Challenges in ncRNA Research ​

Non-coding RNAs (ncRNAs) play a crucial role in gene regulation, acting as key regulators of gene expression in various biological processes. These molecules, which include long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and other types of small RNAs, have been shown to influence gene expression at multiple levels, including transcriptional and post-transcriptional regulation. For instance, microRNAs regulate gene expression by binding to the 3' untranslated regions of target mRNAs, thereby blocking protein translation or inducing mRNA degradation [56]. In contrast, long non-coding RNAs exhibit a broader range of functions, including serving as molecular scaffolds, decoys, and epigenetic regulators [56].

The therapeutic implications of ncRNAs are significant, particularly in the context of various diseases, including cardiovascular diseases and cancer. Recent research highlights the potential of ncRNAs as novel therapeutic targets. For example, specific ncRNAs have been identified as critical regulators of cardiovascular risk factors and cell functions, positioning them as important candidates for improving diagnostics and prognostic assessments in cardiovascular diseases [49]. Additionally, the development of RNA interference (RNAi) drugs targeting specific ncRNAs has shown promise in clinical trials, with applications such as lowering LDL cholesterol and treating cardiac amyloidosis [49].

However, the field of ncRNA research faces several challenges. One significant hurdle is the complexity of the ncRNA landscape itself, which includes a diverse array of RNA species with varying functions and regulatory mechanisms. Understanding the precise roles of these molecules in gene regulation and their interactions with other cellular components remains a critical area of investigation [57]. Furthermore, translating ncRNA research into clinical applications is complicated by issues related to the delivery of RNA-based therapeutics, potential off-target effects, and the need for improved tissue specificity and cellular uptake [56].

In summary, non-coding RNAs are integral to gene regulation, with emerging therapeutic potentials in treating various diseases. Future research must address the challenges associated with ncRNA complexity and therapeutic application to unlock their full potential in clinical settings.

7 Conclusion ​

This review highlights the multifaceted roles of non-coding RNAs (ncRNAs) in gene regulation, emphasizing their significance in various biological processes and disease mechanisms. Key findings indicate that ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are essential regulators of gene expression, influencing transcriptional, post-transcriptional, and epigenetic processes. Current research has established the diverse classifications and biogenesis pathways of ncRNAs, which underlie their complex interactions within cellular regulatory networks. The dysregulation of ncRNAs is associated with numerous pathological conditions, particularly cancer, cardiovascular diseases, and neurological disorders, where they can act as oncogenes, tumor suppressors, or biomarkers for disease progression. Future research should focus on elucidating the precise mechanisms of ncRNA action and exploring their potential as therapeutic targets. Advances in RNA-based therapies could pave the way for novel treatment strategies, enhancing precision medicine approaches in the management of diseases linked to ncRNA dysregulation. Overall, the continued exploration of ncRNAs holds promise for developing innovative diagnostic and therapeutic interventions, significantly impacting health outcomes.

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