Lin28/Let-7 Interaction in Stem Cell and Cancer Biology

The Lin28 proteins, Lin28A and Lin28B, form a conserved regulatory circuit with the let-7 family of microRNAs that governs cell fate, differentiation and oncogenesis. In pluripotent stem cells, Lin28 binds the terminal loop of primary and precursor let-7 transcripts, recruiting terminal uridylyltransferases to block Dicer- and Drosha-mediated processing. This suppression of let-7 maintains high levels of pluripotency factors and supports self-renewal. Conversely, the emergence of mature let-7 promotes cell cycle exit and differentiation by repressing targets such as HMGA2, MYC and RAS. Dysregulation of this axis in adult tissues underlies tumour initiation and progression: overexpressed Lin28 or reduced let-7 tilts the balance towards proliferation, stemness and metastasis. Beyond this canonical model, Lin28A can mediate liquid-liquid phase separation in the nucleolus, while structural studies reveal how Lin28 influences terminal uridylation choices on pre-let-7. Together, these mechanisms integrate post-transcriptional control with subcellular organisation to orchestrate developmental programmes and, when aberrant, drive cancer.

Research from Nature Portfolio

Recent studies demonstrate that Lin28A exhibits non-canonical, RNA-independent roles in the nucleolus of embryonic stem cells. Through its intrinsically disordered regions and RNA-binding domains, Lin28A undergoes liquid-liquid phase separation to form condensates that remodel nucleolar architecture, thereby influencing the transition between naive and primed pluripotency states. Mutations in key disordered residues disrupt nucleolar localisation and impair reprogramming efficiency, emphasising a structural basis for cell fate control. In parallel, high-resolution cryo-EM analyses of TUT7 and TUT4 in complex with pre-let-7 and Lin28A have elucidated the molecular determinants of mono- versus oligo-uridylation. These structures reveal how Lin28A clamps pre-let-7 onto uridylyltransferases to promote processive oligo-uridylation and degradation, providing mechanistic insight into how Lin28 fine-tunes let-7 biogenesis and thus cell fate decisions and tumour suppressor activity.

Lin28/Let-7 Interaction in Stem Cell and Cancer Biology publication trend

The graph below shows the total number of articles in lin28/let-7 interaction in stem cell and cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Lin28A/B: RNA-binding proteins that inhibit let-7 microRNA maturation by recruiting terminal uridylyltransferases.

Let-7 microRNAs: A family of tumour-suppressor microRNAs that promote differentiation by repressing oncogenic mRNAs.

Terminal uridylyltransferases (TUT4/7): Enzymes that add uridine residues to the 3′ end of pre-let-7, determining its maturation or degradation.

Liquid-liquid phase separation (LLPS): The process by which biomolecules demix to form concentrated, membrane-less condensates.

Oncofetal regulon: A network of RNA-binding proteins expressed during development and in cancer, whose translation is co-ordinated by Lin28.

References

1. Dynamic nucleolar phase separation influenced by non-canonical function of LIN28A instructs pluripotent stem cell fate decisions. Nature Communications (2024).
2. Liver cancer initiation requires translational activation by an oncofetal regulon involving LIN28 proteins. Journal of Clinical Investigation (2024).
3. Structural basis for activity switching in polymerases determining the fate of let-7 pre-miRNAs. Nature Structural & Molecular Biology (2024).
4. The LIN28/let-7 Pathway in Cancer. Frontiers in Genetics (2017).
5. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors and its effects on the hallmarks of cancer. Molecular Cancer (2015).