Potential landscape decomposes the cell identity conversion in liver regeneration and tumorigenesis [ChIP-seq]

Tumorigenesis, accompanied by tissue regenerative responses, always occurs during mammalian organ injury. In liver, injury context promotes dedifferentiated liver progenitor-like cells (LPLCs) from hepatocytes for regeneration, and also increases the occurrence of hepatocellular carcinoma (HCC). However, little is known about the contribution of injury specific LPLCs to tumorigenesis. Here, by using lineage tracing model, we have demonstrated that LPLCs are highly susceptible to oncogene-induced tumorigenesis. By using quantitative landscape of differentiation dynamics (LDD) model, we have constructed potential landscape of liver regeneration and tumorigenesis via scRNA-seq data, in order to predict distinct regulations of cell fate decisions. Applying this landscape with in vivo validation by transgenic mouse model, we have found blocking Wnt activation not only inhibits tumorigenesis, but also decreases LPLCs. Surprisingly, by using least action pathway analysis, we have decomposed regeneration and tumorigenesis routes, and found EP300 is specifically involved in tumorigenesis, which is further supported by in vivo EP300-knockout model and EP300 inhibitor assays. These findings might be applied as a framework to find tumor-specific regulators and develop strategies specifically inhibiting tumor initiation while leaving tissue regeneration unaffected. We collected primary hepatocytes via perfusion as reported from normal (WT mice for denoting normal liver-derived cells, n=2) and DDC-injured (Sox9-EGFP mice to trace hepatocyte-derived Sox9-positive LPLC, n=2) liver, HCC cells are collected from 5 months of DDC+cMet treatment Sox9-CreERT2:Rosa26-mTmG, and performed ChIP-SEQ