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

BMC Genomics

Filip Garbicz¹  Eugeniusz Tralle²  Maciej Migdał²  Katarzyna Zofia Kędzierska²  Cecilia Lanny Winata²  Karim Abu Nahia²  Michał Pawlak³  Katarzyna Piwocka⁴  Łukasz Bugajski⁴ 

[1] Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, ul. Indiry Gandhi 14, 02-776, Warsaw, Poland;Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA;International Institute of Molecular and Cell Biology in Warsaw, Laboratory of Zebrafish Developmental Genomics, 4 Ks. Trojdena Street, 02-109, Warsaw, Poland;International Institute of Molecular and Cell Biology in Warsaw, Laboratory of Zebrafish Developmental Genomics, 4 Ks. Trojdena Street, 02-109, Warsaw, Poland;Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, ul. Indiry Gandhi 14, 02-776, Warsaw, Poland;Nencki Institute of Experimental Biology, Laboratory of Cytometry, Warsaw, Poland;

关键词: Liver;    Hepatocytes;    Stellate cells;    Endothelial cells;    Chromatin;    Transcriptomics;    ATAC-seq;    RNA-seq;    Genomics;    Epigenomics;    Zebrafish;   

DOI  :  10.1186/s12864-021-08173-1

来源: Springer

【 摘 要 】

BackgroundLiver 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.ResultsIn 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.ConclusionOur 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.

【 授权许可】

CC BY