LINE1 RNAS COORDINATE RIBOSOME BIOGENESIS AND CHROMATIN ORGANIZATION TO SUSTAIN CELLULAR QUIESCENCE

Cellular quiescence is a reversible and actively maintained state that enables diverse cell types—including adult stem cells, hepatocytes, and T lymphocytes—to transiently suspend proliferation while preserving the ability to rapidly re-enter the cell cycle upon stimulation. In T lymphocytes, the controlled transition from quiescence to activation is essential for effective immune responses, whereas dysregulated re-entry into a quiescent-like state contributes to dysfunction and exhaustion in chronic disease. Yet how the nuclear environment coordinates chromatin organization, biosynthetic restraint, and readiness for rapid activation remains incompletely understood. Transposable elements, which constitute nearly half of the human genome, have recently emerged as regulators of nuclear architecture. Among them, LINE1-derived transcripts interact with chromatin regulators and nucleolar proteins, suggesting roles in linking chromatin state to nucleolar activity. In parallel, the formation of biomolecular condensates via RNA–protein phase separation has been recognized as a central principle organizing nuclear functions such as transcriptional control, heterochromatin architecture, and ribosome biogenesis. Here, we identify a chromatin condensate-based mechanism through which LINE1 RNAs support cellular quiescence. In T lymphocytes, LINE1 transcripts associate with KAP1 and Nucleolin (NCL) to assemble chromatin-associated condensates that perform two major functions: they maintain T cell activation genes in a poised chromatin state, preserving an accessible yet restrained configuration compatible with rapid induction upon stimulation, and they limit ribosome biogenesis by sequestering NCL from the nucleolus, thereby reducing RNA Polymerase I activity and rRNA synthesis. In addition, LINE1 disrupts KAP1–HP1α interactions, reshaping heterochromatin and reinforcing gene-silencing domains. In chronically stimulated tumor-infiltrating lymphocytes, aberrant LINE1 reactivation drives the formation of dysfunctional condensates associated with impaired nucleolar activity; disrupting these assemblies restores rRNA synthesis and protein production. Finally, we show that this mechanism also operates in mouse hepatocytes, where LINE1 similarly modulates chromatin organization and nucleolar activity, indicating that LINE1 functions as a general hub integrating gene regulation, ribosome biogenesis, and cellular homeostasis across quiescent cell types from different tissues and species.