GENOMIC LINEAGE TRACING TO UNDERSTAND TISSUE REMODELING IN MURINE AND HUMAN LIVER

• Applicants: Professor Dr. Jochen Hampe; Privatdozentin Dr. Madlen Matz-Soja; Professor Dr. Daniel Seehofer
• Subject Area: Gastroenterology ; Human Genetics
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 402694925

• Final Report Year: 2024

Final Report Abstract

We report the first combined positional analysis of transcriptomes and methylomes across three zones (pericentral, intermediate and periportal) of healthy human liver and fibrosis progression. We identify pronounced anti-correlated transcriptional and methylation gradients including a core of 271 genes controlling zonated metabolic and morphogen networks and observe a prominent porto-central gradient of DNA methylation at binding sites of 46 transcription factors in the healthy liver. The gradient includes an epigenetic and transcriptional Wnt signature supporting the concept of a pericentral hepatocyte regeneration pathway under steady-state conditions. We observe a molecular reorganization of both layers in fibrotic liver tissue. Pericentral genes become progressively downregulated and periportal genes upregulated leading to the loss of transcriptional zonation in fibrotic samples. For DNA methylation we observe a striking remodeling of the epigenetic landscapes, particularly in fibrosis-specific differentially methylated regions associated with pro-inflammatory pathways. Our findings demonstrate that both the progressive loss of transcriptional hepatic zonation and the overall remodeling of DNA methylation in fibrotic liver tissue cause a portalization phenotype of pericentral hepatocytes, which can be seen as a major hallmark of progressed liver fibrosis in MASLD. In addition we established a cell atlas of the regenerating human liver after portal vein embolization (PVE). We find that PVE alters portal-central zonation of hepatocytes and endothelial cells. Embolization upregulates expression programs associated with development, cellular adhesion and inflammation across cell types. Analysis of inter lineage crosstalk revealed key roles for immune cells in modulating regenerating tissue responses. In addition, our research made significant contributions to understand the zoning of morphogenetic signaling pathways such as Wnt/β-Catenin and Hedgehog (Hh). These findings offer new insights into the regulation of liver metabolism and the interplay between these crucial pathways. Thereby, our findings reveal that in a healthy liver, the Wnt and Hh pathways act largely complementary to each other, with Wnt signaling predominantly active in the pericentral zone and Hh signaling in the periportal zone. In addition to that, we investigate transcriptional changes between the periportal (PP) and pericentral (PZ) zones, we performed laser microdissection followed by RNA sequencing on mice subjected to a highfat diet. This diet induces steatosis, fibrosis, and cirrhosis, making this mouse model particularly suitable given the significant progression of obesity and associated liver fat accumulation. The results of this part indicate distinct transcriptional profiles between the PP and PZ zones, highlighting sex-specific responses to Western diet-induced liver damage for several liver functions like liver lesions and the development of liver tumors.

Publications

• Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control. Nature Communications, 9(1).
  Brosch, Mario; Kattler, Kathrin; Herrmann, Alexander; von Schönfels, Witigo; Nordström, Karl; Seehofer, Daniel; Damm, Georg; Becker, Thomas; Zeissig, Sebastian; Nehring, Sophie; Reichel, Fabian; Moser, Vincent; Thangapandi, Raghavan Veera; Stickel, Felix; Baretton, Gustavo; Röcken, Christoph; Muders, Michael; Matz-Soja, Madlen; Krawczak, Michael ... & Hampe, Jochen
  
• Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human. Cell Reports, 29(13), 4553-4567.e7.
  Kolbe, Erik; Aleithe, Susanne; Rennert, Christiane; Spormann, Luise; Ott, Fritzi; Meierhofer, David; Gajowski, Robert; Stöpel, Claus; Hoehme, Stefan; Kücken, Michael; Brusch, Lutz; Seifert, Michael; von Schoenfels, Witigo; Schafmayer, Clemens; Brosch, Mario; Hofmann, Ute; Damm, Georg; Seehofer, Daniel; Hampe, Jochen ... & Matz-Soja, Madlen
  
• Loss of hepatic Mboat7 leads to liver fibrosis. Gut, 70(5), 940-950.
  Thangapandi, Veera Raghavan; Knittelfelder, Oskar; Brosch, Mario; Patsenker, Eleonora; Vvedenskaya, Olga; Buch, Stephan; Hinz, Sebastian; Hendricks, Alexander; Nati, Marina; Herrmann, Alexander; Rekhade, Devavrat Ravindra; Berg, Thomas; Matz-Soja, Madlen; Huse, Klaus; Klipp, Edda; Pauling, Josch K.; Wodke, Judith AH; Miranda, Ackerman Jacobo; Bonin, Malte von ... & Subramanian, Pallavi
  
• Cell atlas of the regenerating human liver after portal vein embolization.
  Brazovskaja, Agnieska; Gomes, Tomás; Körner, Christiane; He, Zhisong; Schaffer, Theresa; Eckel, Julian Connor; Hänsel, René; Santel, Malgorzata; Denecke, Timm; Dannemann, Michael; Brosch, Mario; Hampe, Jochen; Seehofer, Daniel; Damm, Georg; Camp, J. Gray & Treutlein, Barbara
  
• Diploid hepatocytes drive physiological liver renewal in adult humans. Cell Systems, 13(6), 499-507.e12.
  Heinke, Paula; Rost, Fabian; Rode, Julian; Trus, Palina; Simonova, Irina; Lázár, Enikő; Feddema, Joshua; Welsch, Thilo; Alkass, Kanar; Salehpour, Mehran; Zimmermann, Andrea; Seehofer, Daniel; Possnert, Göran; Damm, Georg; Druid, Henrik; Brusch, Lutz & Bergmann, Olaf