Priasha Dutta, Amity University Kolkata

The story of RNA

Our understanding of the molecular biology of gene regulation has come a long way since the term “The Central Dogma” was coined in 1957. While early research was dedicated to comprehending DNA and proteins mostly, RNA (Ribonucleic Acid) biology has since gained a growing amount of attention in recent years. The arrival of Next-Generation Sequencing (NGS) technologies has led to the discovery of multiple novel RNA species. The viewpoint has also changed from RNA as an intermediary for protein synthesis to the multiple roles that RNAs play in important cellular processes and the pathogenesis of complex diseases like cancer. The increased transcript and protein expression of the major oncogenes, instead of the genomic alterations, has been linked to cancer development. This implies that the dysregulation of RNA expression is a crucial aspect of cancer development. In addition to this, some of these regulators can modify RNA length and nucleotide integrity, thereby influencing RNA function. Any disturbance occurring after the transcriptional process in the case of cancer is likely to impact multiple target RNAs directly or indirectly (discussed later on) to initiate cancer development or progression, hence creating what is known as “The Butterfly Effect”. 

The microRNA world

In the following years, numerous independent groups of researchers have described the existence of an additional phenomenon of regulation, one that is controlled by and dependent on– microRNAs, abbreviated as miRNAs. Although a vast majority of studies have explored the impact of miRNAs in the regulation and onset of various diseases, something that’s lesser known is how the miRNA targets in turn affect the regulation of the miRNAs. These are the transcripts that contain the binding sites for common miRNAs that can modulate the available pool of miRNAs and thus reciprocally regulate each other, hence acting as miRNA ‘sponges’ or ceRNAs (competing endogenous RNAs). For instance, an increase in the expression of a specific RNA would sponge miRNAs away from their respective ceRNAs, thus leading to their upregulation. In this kind of interaction, each RNA is usually targeted by multiple miRNAs, forming a ceRNA network (ceRNET) that bridges many independently expressed RNAs and miRNAs into an intricately and vastly connected network. Any change in the ceRNA or miRNA expression could lead to the subsequent disbalance of ceRNETs. Furthermore, RNA alterations that affect miRNA target recognition could destroy the miRNA binding sites, leading to a total disruption of the ceRNET equilibrium. 

Future Perspectives

This unique sensitivity of ceRNA networks along with their potential Butterfly Effect on transcriptomic equilibrium has led to a spirited debate about the optimal conditions for ceRNA crosstalk. The affinity for specific target sites, endogenous miRNA/target pool ratios, and cooperative binding of proximal sites for the same or different miRNAs are supposedly the determinants for optimal ceRNA crosstalk. A lot is yet to be known about stoichiometry, subcellular localization, and other factors behind the effectiveness of ceRNA regulation.  Multiple studies have identified specific miRNA/ceRNA networks as the key players in the development of several cancers. In recent years, massive breakthroughs have progressed our understanding into the various aspects of RNA regulation and processing which have major implications for RNA stability, sequence composition, and thus the subsequent clinical applications. 

Also read:D614G: NEW CORONAVIRUS MUTATIONS MAKES THE VIRUS EIGHT TIMES MORE INFECTIOUS

REFERENCES- 

1. Iorio M.V, & Croce C.M. (2012). Causes and consequences of microRNA dysregulation. Cancer Journal (Sudbury, Mass.), 18(3), 215–222. https://doi.org/10.1097/PPO.0b013e318250c001 

2. Desi N, & Tay Y. (2019). The butterfly effect of RNA alterations on transcriptomic equilibrium. Cells, 8(12), 1634. https://doi.org/10.3390/cells8121634

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