Cells in the human body—such as those in the eyes, kidneys, brain, or toes—display striking structural and functional differences, even though their DNA sequences are largely identical. The answer to this fundamental biological question lies not in the mere presence of genes, but in which genes are activated, when, to what extent, and within which cellular context. Current findings indicate that RNA stands at the center of this regulatory framework.
The Dark Matter of the Genome and the RNA Layer of Cellular Identity
In classical biology, DNA was defined as the repository of genetic information, RNA as its temporary messenger, and protein as the final functional product. However, only about 2% of the human genome encodes proteins. The remaining vast majority consists of non–protein-coding sequences, long considered nonfunctional but now referred to as the “dark matter” of the genome. A significant portion of these regions is transcribed into noncoding RNA molecules that do not produce proteins but instead exert powerful regulatory functions.
From small regulatory RNAs to long noncoding RNAs, this broad molecular repertoire controls whether genes are turned on or off, their level of expression, and their timing. Cellular differentiation does not occur through the sudden activation of single genes; rather, it emerges from the temporal reconfiguration of multilayered RNA interaction networks. Whether a cell becomes a neuron or a liver cell depends on the dynamic balance of these RNA networks.
Another critical dimension of this regulation involves RNA modifications. After RNA molecules are synthesized, they can acquire various chemical marks. These modifications determine RNA stability, intracellular localization, and protein production capacity. Unlike epigenetic marks on DNA, RNA modifications are not necessarily permanent; they can change rapidly in response to the physiological state of the cell. This dynamic control at the RNA level enables cellular identity to be regulated in a flexible and environmentally responsive manner.
For example, under normal conditions, certain RNA modification patterns may trigger the degradation of RNAs that encode stress-response proteins. When a cell enters a state of stress, this pattern is reprogrammed; the relevant RNAs become stabilized, and the production of protective proteins increases. Such reprogramming mechanisms allow the cell to transition into new functional states.
Epitranscriptomic Dynamics and Cellular Response Mechanisms
The chemical diversity of RNA modifications is also noteworthy. More than fifty distinct chemical marks on RNA have been identified within cells, collectively referred to as the “epitranscriptome.” In particular, increased levels of specific modifications in transfer RNAs involved in protein synthesis have been shown to be associated with cancer development, resistance to chemotherapy, and developmental and neurological diseases. These findings underscore that RNA-based regulation is central not only to fundamental biology but also to clinical applications.
Within this framework, the internationally coordinated RNome initiative aims to systematically map all RNA species present in human cells and their chemical modifications.1 The Human Genome Project marked a turning point in biology by revealing the DNA sequence. The RNome approach, by contrast, seeks to comprehensively define how that sequence is used—identifying which RNA species are produced under specific cellular conditions and how they are chemically regulated. The goal is not merely to generate an inventory of RNAs, but to uncover regulatory differences between healthy and diseased cells in order to lay the groundwork for new diagnostic and therapeutic strategies.
RNA provides a dynamic control layer that determines when and how the potential stored in DNA is realized. Cellular diversity does not arise from executing a fixed list of genes, but from the temporal and contextual orchestration of RNA networks. As RNome maps expand, they are expected to deepen our understanding of the molecular logic underlying cellular identity across fields ranging from developmental biology to cancer research.
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