Study Reveals Nuclear RNA Homeostasis Promotes Systemic Orchestration of Cell Fate and Aging

A research team from Tsinghua University School of Medicine in China published a research paper titled "Nuclear RNA homeostasis promotes systems-level coordination of cell fate and senescence" in the journal Cell Stem Cell. This study demonstrates that nuclear RNA homeostasis contributes to the systemic coordination of cell fate and aging. Depletion of RNA exosomes leads to destruction of nuclear RNA, which leads to systemic functional decline, changes in cellular status, and promotes aging.

The nucleus serves as a central command center that houses and decodes the genome through transcription. This makes RNA available for cytoplasmic protein synthesis and the coordination of life processes that define different cellular states. Approximately half of the nuclear volume is occupied by chromatin, while the remaining space contains compressed ribonucleoprotein (RNP) granules. Transcription occurs at the interface between the nucleolus and perichromatin, producing RNA that crosses the gap between chromatin and chromatin. In the nucleolus, RNA polymerase I (Pol I) directs the transcription of ribosomal RNA (rRNA), resulting in the production of small (40S) and large (60S) rRNA-protein particles. These abundant ribosomal subunits are then exported to the cytoplasm and assembled into functional ribosomes (80S) for protein translation.

Surrounding chromatin, the RNA polymerase Pol II is responsible for the production of messenger RNA (mRNA) and a wide range of non-coding RNA (ncRNA) transcripts. mRNA accounts for only 1% of the genome. It is highly expressed and efficiently spliced, and is exported from the nucleus to the cytoplasm and then translated into proteins. In contrast, ncRNA originates from the vast majority of genomes and exhibits characteristics such as low expression, minimal splicing, rapid decay, and nuclear retention. These diverse ncRNAs include long non-coding RNAs (lncRNAs).

The biogenesis of mRNA coincides with transcription. When nascent RNA is produced from translocating RNA polymerase on a chromatin template, it binds to proteins to form heterogeneous RNP (hnRNP) particles within the nucleus. Some of these mRNA-associated hnRNP particles undergo additional RNA processing, remodeling, and protein deposition, ultimately forming mature messenger RNPs (mRNPs) and exported to the cytoplasm. In contrast, ncRNA-associated hnRNPs (ncRNPs) remain in the nucleus, where the ncRNA components are degraded. Monitoring systems ensure the accuracy of mRNA use for protein synthesis, and pre-mRNAs with processing defects decay in the nucleus and accept the ncRNA fate.

Coordinating the production, processing, degradation and nuclear export of RNA ensures the balance between different types of RNA (rRNA, mRNA and ncRNA) and maintains RNA homeostasis in the nucleus. Nuclear ncRNPs, together with exported mRNPs and ribosomal subunits, are localized to form a dynamic network that extends throughout the nucleoplasm, tightly wrapping and penetrating chromatin. This nuclear RNP network provides a structural framework that supports dynamic interactions and enzymatic reactions, potentially affecting chromatin organization and essential nuclear processes such as transcription, RNA processing, and nuclear transport. However, the functional implications of nuclear RNA homeostasis in the RNP network and its impact on nuclear and cellular functions remain unclear.

The RNA exosome complex processes pre-rRNA by removing external and internal transcribed spacers (ETS and ITS) and degrades erroneous rRNA and pre-mRNA, intronic RNA, and different types of ncRNA. This exosome activity contributes to the rapid turnover of nuclear ncRNAs and serves as a quality control mechanism for rRNA and mRNA biogenesis, ensuring the fidelity of functional RNA molecules. The activity and specificity of the RNA exosome depend on its binding to adapter protein complexes (e.g., TRAMP, NEXT, PAXT), which respectively target specific RNA substrates (e.g., precursor rRNA, nuclear ncRNA, and aberrant mRNA). The conserved RNA helicase MTR4 serves as an adapter for RNA exosomes and promotes targeted degradation by unwinding substrate RNA and promoting oligoadenylation.

Mutations in key components of the exosome, including EXOSC2, EXOSC3, and EXOSC8, are associated with severe neurological disorders and progeria in humans. However, the molecular consequences of impaired RNA catabolism under pathological conditions remain unclear. Compared with differentiated cells, pluripotent embryonic stem cells (ESCs) exhibit unique characteristics, including high Pol I and Pol II transcriptional activity, enhanced ribosome biogenesis and translation levels, global loose chromatin knots, and significantly enlarged nucleoli. To explore the interaction between nuclear RNA homeostasis and cellular processes, the research team established a controllable protein degradation system in mouse pluripotent embryonic stem cells (ESCs), targeting an important exosome component EXOSC2 to interfere with RNA catabolism.

The study's findings highlight the critical importance of RNA catabolism in maintaining the delicate balance between nuclear RNA and proteins in the original nuclear RNA environment. This homeostasis is critical for coordinating critical processes such as transcription, ribosome biogenesis, translation, and genome organization, thereby optimizing cellular function. Disruption of this coordination can profoundly affect nuclear and cellular functions, leading to systemic decline, compromising the properties of pluripotent cells, and accelerating the onset of premature aging.

Figure 1. The dynamic turnover of nuclear RNA orchestrates crosstalk between essential processes to optimize cellular function. (Han X, et al., 2024)

Specifically, the study observed that depletion of RNA exosomes in embryonic stem cells significantly affects the transcriptome and proteome, leading to loss of pluripotency and the onset of premature senescence. Mechanistically, depletion of exosomes triggers acute nuclear RNA aggregation and disrupts nuclear RNA-protein balance. This interference limits the availability of nuclear proteins, hinders polymerase initiation and engagement, and reduces gene transcription. At the same time, it rapidly disrupts nucleolar transcription, ribosomal processes, and nuclear export, leading to translation shutdown. Long-term exosome depletion also induced nuclear structural changes similar to those in senescent cells.

These effects suggest that dynamic turnover of nuclear RNA orchestrates crosstalk between fundamental processes to optimize cellular function. Disruption of nuclear RNA homeostasis can lead to systemic functional decline, alter cellular status, and promote aging.

Reference

Han X, et al. Nuclear RNA homeostasis promotes systems-level coordination of cell fate and senescence. Cell Stem Cell, 2024.