The RNA-binding protein TRIM71 Promotes Supporting Cell Reprogramming and Hair Cell Regeneration by Activating Sall4.
Li Lin L, Huang He H, Meng Shixian S, Liu Xingyu X et al.
Hair cell (HC) loss in the auditory organ (cochlea) is irreversible and represents the leading cause of deafness in humans. The absence of HC regeneration is primarily due to the limited plasticity of cochlear supporting cells (SCs). Using a novel doxycycline-inducible TRIM71 transgenic mouse model, this study demonstrates that overexpression of the RNA-binding protein TRIM71 promotes spontaneous cochlear HC regeneration in neonatal mice. Experiments in cochlear organoids indicate that TRIM71 reprograms SCs into progenitor-like cells and that this reprogramming is further enhanced by coactivation of follistatin (FST). FST augments TRIM71-induced increases in chromatin accessibility at progenitor and HC-specific gene loci, facilitating their transcriptional activation in SCs. Notably, FST also enhances TRIM71-induced reactivation of Sall4, which, like Trim71, is highly expressed in early otic progenitors. Using cochlear organoids and explants, we show that the early otic transcription factor SALL4 is required for TRIM71-induced HC formation. By contrast, SALL4 overexpression inhibits HC formation by maintaining reprogrammed SCs in an undifferentiated, proliferative state. These findings establish TRIM71 as an activator of HC regeneration in vivo, provide mechanistic insights into TRIM71's role in SC reprogramming, and identify SALL4 as its essential effector. The mammalian cochlea lacks intrinsic capacity for hair cell (HC) regeneration, a deficiency that underlies the permanent nature of hearing loss. Using a novel inducible transgenic mouse model, we demonstrate that reactivation of Trim71, an otic progenitor gene, promotes HC regeneration in perinatal mice. TRIM71 induces an otic progenitor-like transcriptional program in supporting cells (SCs) through Sall4 activation, while concurrently initiating mesenchymal gene expression. This conflicting transcriptional state is resolved by co-activating follistatin, which suppresses mesenchymal conversion genes and increases chromatin accessibility at progenitor- and HC-specific gene loci. Collectively, our findings establish a mechanistic framework wherein TRIM71 functions as a key regulator of SC plasticity and identify the transcription factor SALL4 as a critical downstream effector in HC regeneration.