Poster Presentation 43rd Lorne Genome Conference 2022

UnNrf(2)ing the adaptive transcriptional responses following liver injury and during liver regeneration (#259)

Vicky Tan 1 , Anthony Karamalakis 1 , Chih Chan 1 , Andrea Gillespie 1 , Mark A Dawson 1 2 3 , Andrew Cox 1 4
  1. Peter MacCallum Cancer Centre, Parkville, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC
  3. Center for Cancer Research, The University of Melbourne, Parkville, VIC, Australia
  4. Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, Australia

The liver is indispensable for metabolism, digestion, and nutrient storage. Impressively, it is the only human organ with the unique ability to regenerate following injury or partial removal. Following injury, liver regeneration is driven by normally quiescent hepatocytes that rapidly proliferate to restore tissue architecture and function. Impaired liver regeneration is a significant clinical burden as treatment for patients with liver diseases, such as hepatocellular carcinoma (HCC) relies heavily on successful liver transplantation and subsequent regrowth. Consequently, understanding the cellular mechanisms and molecular underpinnings of liver regeneration is critical. The transcription factor, Nrf2 is known to regulate the expression of genes that are critical for antioxidative defence, detoxification, and metabolism under stressed conditions. More recently, Nrf2 has been identified to play a role in sensing liver injury and driving liver regeneration. Acetaminophen (APAP) is a commonly used analgesic, and its overuse is one of the major causes of acute liver failure in the United States. Consequently, we use APAP to induce liver injury in both zebrafish larvae and adults­­­ to study Nrf2’s role in remodelling the adaptive transcriptional landscape following injury. RNA-sequencing on dissected livers from larvae exposed to APAP revealed that the pentose phosphate pathway may be critical in both sensing injury and driving a regenerative response following 12 hours of liver injury. We have also developed a new transgenic zebrafish to study nascent transcripts of hepatocytes following APAP-exposed liver injury in vivo through SLAMitseq. This allows us to understand the transcriptional changes following liver injury at times that have not previously been possible through traditional RNA sequencing approaches. Ultimately, my project aims to better understand hepatocytes’ immediate response following injury and to identify pathways that may co-opt with Nrf2 to improve liver injury response and regeneration for patients with liver disease and cancer.