BioProject

Partial hepatectomy (PH) imposes increased protein synthesis demands on remaining hepatocytes. More...

Partial hepatectomy (PH) imposes increased protein synthesis demands on remaining hepatocytes. Activation of IRE1α, a key sensor of endoplasmic reticulum (ER) stress, elicits XBP1 mRNA splicing and production of XBP1 protein, a main trigger of the unfolded protein response (UPR). Using genome-wide ChIPseq analysis we have explored the role of XBP1 during liver regeneration. XBP1 was induced in liver at 6h after PH in an IL-6 dependent manner. After PH, XBP1 silencing caused persistent ER stress, defective acute phase response (APR), increased hepatocellular damage and regenerative delay. At 6h post-PH, XBP1 bound an increased number of genes implicated in proteostasis, APR, metabolism, antioxidant defense and DNA damage response (DDR). ). XBP1 was linked to regulatory sequences containing canonical UPR motifs as well as motifs characteristic of other nuclear factors suggesting molecular interactions during liver regeneration. Upon PH, XBP1 bound the promoter of STAT3, a molecule downregulated in XBP1-silenced livers. XBP1 was indispensable for ser727-STAT3 phosphorylation, a post-translational modification implicated in cell proliferation and DNA damage repair. During active DNA replication XBP1 deficient livers showed high levels of the DNA double-strand break marker γ-H2AX, in association with defective upregulation of Eme1 and Fen1, two main executors of DDR. In conclusion, XBP1 is induced after PH and co-regulates UPR, APR and DDR during liver regeneration. Overall design: Peak calls from XBP1 ChIPseq data from 8 samples, including Liver from C57 mice Less...