Multi-omics analyses of early liver injury reveals cell-type-specific transcriptional and epigenomic shift

Abstract

Background Liver fibrosis is a wound-healing response to tissue injury and inflammation hallmarked by the extracellular matrix (ECM) protein deposition in the liver parenchyma and tissue remodelling. Different cell types of the liver are known to play distinct roles in liver injury response. Hepatocytes and liver endothelial cells receive molecular signals indicating tissue injury and activate hepatic stellate cells which produce ECM proteins upon their activation. Despite the growing knowledge on the molecular mechanism underlying hepatic fibrosis in general, the cell-type-specific gene regulatory network associated with the initial response to hepatotoxic injury is still poorly characterized. Results In this study, we used thioacetamide (TAA) to induce hepatic injury in adult zebrafish. We isolated three major liver cell types - hepatocytes, endothelial cells and hepatic stellate cells - and identified cell-type-specific chromatin accessibility and transcriptional changes in an early stage of liver injury. We found that TAA induced transcriptional shifts in all three cell types hallmarked by significant alterations in the expression of genes related to fatty acid and carbohydrate metabolism, as well as immune response-associated and vascular-specific genes. Interestingly, liver endothelial cells exhibit the most pronounced response to liver injury at the transcriptome and chromatin level, hallmarked by the loss of their angiogenic phenotype. Conclusion Our results uncovered cell-type-specific transcriptome and epigenome responses to early stage liver injury, which provide valuable insights into understanding the molecular mechanism implicated in the early response of the liver to pro-fibrotic signals.

Knockdown of Yap attenuates TAA-induced hepatic fibrosis by interaction with hedgehog signals

“…In this work, to dissect the molecular regulation mechanisms during the initiation of hepatic fibrosis process, the model of TAA‐induced liver injury in embryonic and adult zebrafish were utilized following the administration routes and time points as reported (Chuang et al 2016; Turola et al 2015; Migdał et al 2021; Amali et al 2006b; Katoch and Patial 2021). In summary, this study demonstrates that cross talking of Yap and Hh plays a critical role in liver fibrotic response and provides new theoretical insight concerning the mechanisms of fibrosis progression.…”

Investigating chromatin accessibility during development and differentiation by ATAC-sequencing to guide the identification of cis-regulatory elements

“…In the mouse, cardiac regenerative capacity is limited to neonatal stages. However, in adult zebrafish several tissues can regenerate, and this has been used to determine chromatin accessibility, including in the heart following cryoinjury or ventricular resection injury [ 64 , 67 ], or the liver [ 68 ], or tail fin [ 69 ]. In regenerating cardiomyocytes, chromatin accessibility changes extensively [ 64 ], this may be regulated by the AP-1 TFs, Junb and Fosl1, found to be enriched in ATAC-seq peaks.…”