miRNA: starting a new era of understanding gene expression regulation—an introduction of the 2024 Nobel Prize in Physiology or Medicine

<sec><p indent="0mm">The 2024 Nobel Prize in Physiology or Medicine was awarded to American scientists Victor Ambros and Gary Ruvkun for their groundbreaking discovery of microRNAs (miRNAs) and their pivotal role in post-transcriptional gene regulation. Gene expression regulation is essential for cell fate determination and cellular activities within organisms, ensuring the maintenance of normal physiological functions and adaptability to environmental changes. miRNAs are a class of non-coding small RNAs that precisely regulate target gene expression through sequence complementarity, playing pivotal roles in development, immune responses, and disease progression. </sec><sec> The journey of miRNA discovery began in 1993 when Victor Ambros identified the first miRNA, lin-4, in the model organism <italic>Caenorhabditis elegans</italic>. Meanwhile, Gary Ruvkun’s laboratory localized the target sequence recognized by lin-4 to the 3ʹ untranslated region (3ʹ-UTR) of the <italic>lin-14</italic> mRNA. In 2000, Gary Ruvkun identified the second miRNA, let-7, a conserved miRNA across animal species. This discovery highlighted the universal regulatory role of these short RNAs and further advanced the field of miRNA research. By 2001, multiple miRNAs were identified in diverse organisms, leading to the formal introduction of the term “microRNA”. The field expanded rapidly with the advent of high-throughput sequencing technologies, resulting in the identification of numerous miRNAs across various species. </sec><sec> miRNAs are endogenous non-coding small RNAs, typically 20-24 nucleotides long, that play key roles in gene expression regulation. Their biogenesis involves several finely regulated steps. In animals, primary miRNA transcripts (pri-miRNAs) are processed in the nucleus by the RNase III enzyme Drosha into precursor miRNAs (pre-miRNAs), which are then exported to the cytoplasm and further processed by Dicer into mature miRNA:miRNA* duplexes. One strand within the duplex is incorporated into the RNA-induced silencing complex (RISC), and guides the RISC to target mRNAs for degradation or translational inhibition. In contrast, in plants, the processing of pri-miRNAs into mature duplexes and the assembly of RISC both take place within the nucleus, after which the RISC is exported to the cytoplasm. </sec><sec> The mechanism of miRNA action differs between animals and plants. In animals, miRNAs recognize target mRNAs via their seed region (the 2nd to 8th nucleotides from the 5ʹ end) and are thought to predominantly bind to the 3ʹ-UTR of target mRNAs, thereby inhibiting translation or promoting mRNA degradation. In contrast, plant miRNAs exhibit near-perfect complementarity to target mRNAs, leading to mRNA cleavage and translation inhibition. </sec><sec> The discovery of miRNAs has revolutionized our understanding of gene expression regulation. This breakthrough earned Victor Ambros and Gary Ruvkun the Nobel Prize. Their research uncovered a novel layer of gene regulation that occurs at the RNA level in the central dogma of molecular biology. The significance of miRNAs extends beyond basic research into clinical and agricultural applications. Numerous miRNA-based therapeutics are currently under development; however, the progress of miRNA therapeutics faces numerous challenges. In agriculture, miRNAs are being utilized to improve crop traits, such as developing high-yield, disease-resistant rice varieties. </sec><sec> The recognition of miRNA research by the Nobel Prize underscores its transformative impact on the field of gene expression regulation. Future research will likely focus on leveraging miRNAs in clinical and agricultural settings, further realizing their potential to benefit human health and agriculture. </sec>