IDDF2024-ABS-0192 METTL1 regulates residual liver regeneration after hepatectomy by mediating tRNA m7G modification

Background

Partial hepatectomy (PHx) is an important treatment for various benign and malignant liver diseases. Post-hepatectomy liver failure (PHLF), which is caused by insufficient volume or quality of the liver, is one of the main causes of death after hepatectomy. Epigenetic modification plays an important role in tissue regeneration and repair. tRNA has been reported to have abundant post-transcriptional modifications, and N7-methylguanosine (m⁷G) modification is one of the most common tRNA modifications. However, the functional and molecular mechanisms of tRNA m⁷G modification in liver regeneration after PHx remain to be determined.

Methods

We constructed 70%PHx mouse models and collected liver tissues at different time points after PHx. Proteomics, m⁷G reduction, cleavage sequencing (TRAC-seq), and ribosome-sequencing were performed to study the level of m⁷G tRNA modification, tRNA expression and mRNA translation efficiency. Subsequently, the biological function and mechanism of m⁷G tRNA modification in regeneration after PHx were studied via conditional knockout mouse models, hydrodynamic and adenovirus transfection overexpression or knockdown mouse models. Furthermore, clinical samples were collected for further verification.

Results

In this study, we found significant residual liver regeneration after 70%PHx, and METTL1 level increased steadily after PHx. Depletion of METTL1 significantly reduced hepatocyte proliferation and impaired residual liver regeneration after PHx, while overexpression of METTL1 promoted residual liver regeneration after PHx. Mechanistically, METTL1 knockdown resulted in a significant decrease in m⁷G tRNA modification levels and m⁷G-modified tRNA expression in regenerated hepatocytes. Multi-omics analysis and functional studies further demonstrated that METTL1 affected residual liver regeneration after PHx by affecting the translation efficiency of the Hippo pathway key protein YAP/TAZ. In addition, overexpression of YAP promoted residual liver regeneration in METTL1 knockdown mouse models after PHx. Clinically, we found that patients with better regeneration efficacy after PHx tended to have higher levels of METTL1.

Conclusions

In summary, METTL1 and its mediated m⁷G tRNA modification promoted the translation level of YAP/TAZ, key proteins of the Hippo pathway, and thus mediated the efficiency of liver regeneration after PHx. Our study uncovers novel mechanisms underlying liver regeneration and provides potential therapeutic targets to override PHLF in PHx.