The gradual discovery of cell-type and context specificity of microRNAs

Since their discovery in the early 1990s, microRNAs (miRNAs) have emerged as pivotal regulators of gene expression, influencing a wide range of biological processes. Early studies focused on understanding the general regulatory functions of miRNAs, but subsequent research has revealed their intricate cell-type and context-specific roles. This gradual process of discovery has unveiled the complexity of miRNA regulation and their functional specificity, contributing significantly to our understanding of development, disease, and tissue-specific regulation.

The journey of miRNA research began with the landmark discovery of lin-4 in Caenorhabditis elegans by Lee et al. (1993). This small RNA was found to regulate the lin-14 gene, introducing the world to miRNAs. However, it was not until subsequent studies that the tissue-specific roles of these molecules were revealed.

A major breakthrough in tissue-specific miRNA expression came with the identification of miR-122 as a liver-specific miRNA by Lagos-Quintana et al. (2002). This finding linked miRNAs to organ-specific functions, shedding light on their role in tissue homeostasis and metabolic regulation. Subsequently, the identification of miR-1 as muscle-specific highlighted the importance of miRNAs in organ development, particularly in muscle differentiation and growth (Chen et al., 2006).

These early discoveries were crucial in shifting the focus of miRNA in different tissues. The realization that miRNAs could have distinct expression patterns depending on the tissue or organ marked the beginning of the concept of miRNA specificity in biological systems.

One of the most studied miRNAs, miR-34a, exemplifies the importance of cellular context in miRNA function. Its role in tumor suppression, particularly through the p53 pathway, was demonstrated in a seminal paper by He et al. (2007). The study showed that miR-34a could induce apoptosis and cell cycle arrest, but these effects were dependent on the cellular context. miR-34a’s ability to mediate different outcomes based on the cell type it operates in underscores the complexity of miRNA regulation.

The context-dependent nature of miR-34a activity was further underscored by Dutta et al. (2007). We demonstrated that miR-34a overexpression could elicit diverse effects on cellular proliferation, depending on the cell type. Our research revealed that miR-34a, a well-established tumor suppressor, exerts variable influences on cell growth. In certain contexts, miR-34a inhibits proliferation by down regulating targets involved in cell cycle regulation and apoptosis. However, the study revealed that miR-34a overexpression does not universally suppress cell growth. In specific cell types, the response was minimal or even paradoxical, suggesting that miR-34a’s effects are intricately tied to the cellular environment.

 Dutta et al. (2007) also conducted an in situ analysis of healthy rat tissues, providing additional evidence for the tissue-specific expression of miR-34a. They observed significant variations in miR-34a levels across different tissues, with cerebral neurons and Purkinje cells exhibiting the highest expression. In contrast, normal renal tubules, hepatocytes, and myocardial cells showed faint expression. This differential expression suggests that miR-34a plays distinct functional roles depending on the tissue type. In tissues where miR-34a is highly expressed, it may be involved in maintaining homeostasis by regulating cell turnover. Conversely, in tissues with lower miR-34a expression, its regulatory role might be less pronounced. These findings reinforce the notion that miR-34a’s effects on cellular processes, including proliferation and cell cycle regulation, are intricately linked to the local cellular context.

The development of next-generation sequencing technologies has revolutionized miRNA research, enabling large-scale studies to catalog miRNA expression across different tissues and cell types. The creation of a mammalian miRNA expression atlas by Landgraf et al. (2007) provided a comprehensive overview of miRNA expression patterns, further supporting the concept of cell-type specificity. By cataloging miRNA expression in a wide range of mammalian tissues, this study highlighted that miRNAs are not only tissue-specific but also highly regulated depending on the cellular environment. This atlas laid the groundwork for understanding miRNA function in a broader, more systemic context.

In addition, studies such as that by Lim et al. (2005), demonstrated that miRNAs could regulate large numbers of target mRNAs in specific tissues. This large-scale regulation highlights the potential of miRNAs to fine-tune gene expression in a context-dependent manner, exerting significant control over cellular processes such as differentiation, metabolism, and apoptosis.

Beyond tissue specificity, miRNAs also play critical roles in developmental and disease-specific contexts. For example, the miRNAs miR-1 and miR-133 have been shown to be essential in cardiovascular development and muscle differentiation (Chen et al., 2006; Zhao et al., 2007). Their context-specific roles in heart and skeletal muscle highlight how miRNAs can regulate tissue-specific developmental processes. Similarly, miR-29 has been found to modulate p53 activity in a context-dependent manner, depending on the cellular environment, as demonstrated by Park et al. (2009).

These findings emphasize that miRNA function cannot be generalized across all cells; rather, their effects are shaped by the intricate interactions within specific cellular and developmental contexts. This context specificity is crucial for maintaining normal physiological function and for understanding the aberrant regulation of miRNAs in diseases like cancer.

The discovery of cell-type and context specificity of miRNAs has been a transformative process in molecular biology. From the initial identification of miRNAs to the realization of their specialized functions in different tissues and cell types, research has revealed that miRNA regulation is highly context-dependent. Studies on miRNAs like miR-34a, miR-122, and miR-1 have underscored the importance of the cellular environment in determining miRNA function. As the field continues to evolve, further exploration of miRNA specificity will undoubtedly uncover new layers of complexity, particularly in understanding diseases and developing targeted therapies. The challenge ahead lies in unraveling how miRNAs interact with diverse cellular networks to maintain homeostasis and how their dysregulation contributes to disease.

Declaration by author

The authors declare that the manuscript was generated with the assistance of ChatGPT, an artificial intelligence program developed by OpenAI. However, the authors are responsible for the content and accuracy of the manuscript.

Acknowledgments

The author would like to express his sincere gratitude to Professor Shinya Toyokuni, MD, PhD, Kyoto University (present location, Nagoya University), Japan, for supporting, guiding, and supervising the discovery of cell-type and context specificity of microRNA-34a.

Ethical approval statement

None to declare.

Data availability

Not applicable.

Informed consent statement

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Conflict of interest

The author declare no competing interests.

Authors’ contribution

Khokon Kumar Dutta contributed to the design and writing of this editorial.