Epigenomic analysis of micro-dissected human liver
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To investigate the underlying molecular principles of metabolic and morphogenic zonation of the human liver lobule, we generated an integrated epigenetic map across three zones (pericentral, intermediate and periportal) by methylation and transcriptomic analysis of hepatocytes captured by laser micro-dissection. We observe a deep link between epigenetic zonation of human liver and a zonated expression of metabolic and morphogenic pathways: Key transcriptionally zonated enzymes in xenobiotic and glutamine metabolism show a strong anticorrelated methylation gradient indicating that zonal expression of these genes is partly controlled by epigenetic programs. Zonated DNA - methylation at binding sites of uniformly expressed transcription factors such as HNF4A and RXRα points to an epigenetic layer in regulatory networks and a zonated activity of their nuclear ligands and drugs such as fibrates and bile acids. The same holds for genes of the wnt morphogen pathway whose expression show a zonated methylation at binding sites of TCF4L2. A strong pericentral expression of LGR5 and AXIN2 and a corresponding expression gradient of the liver progenitor marker TBX3, indicates a predominant pericentral source of hepatocyte regeneration under steady-state conditions in humans. Conversely, the periportal expression of NOTCH and EPCAM at the border to the biliary tree as source of regeneration under injury conditions. Overall our data provide a deep understanding of molecular control of the zonal organisation in the human liver.
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Kathrin Kattler, Alexander Herrmann, Karl Nordström, Sebastian Zeissig, Fabian Reichel, Felix Stickel, Gustavo Baretton, Christoph Röcken, Michael Muders, Michael Krawczak, Gilles Gasparoni, Hella Hartmann, Andreas Dahl, Jörn Walter
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Created: 13th Jul 2021 at 08:18
Last updated: 24th Oct 2022 at 17:05
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https://orcid.org/0000-0002-2104-8076The clinical department of Prof. Dr. med Daniel Seehofer performs more than 200 surgical interventions on the liver annually. Therefore, the group has access to a broad variety of liver tissues as well as corresponding patient, clinical laboratory and characterization data. I lead the experimental work group which has a longstandind expertise in the isolation, characterization and application of primary human liver and hepatoma cells. These cells as well as data generated from established liver ...
Projects: LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI), LiSyM network, LiSyM Scientific Leadership Team (LiSyM-LT), LiSyM-Krebs Partnering, Forschungsnetzwerk LiSyM-Krebs, DEEP-HCC network
Institutions: Universitätsklinikum Dresden - Medizinische Klinik I, Bereich Gastroenterologie & Hepatologie, Zentrum für Informationsdienste und Hochleistungsrechnen (ZIH), Technische Universität Dresden
Projects: The Hedgehog Signalling Pathway (LiSyM-JGMMS), LiSyM PALs, LiSyM network, LiSyM Scientific Leadership Team (LiSyM-LT), LiSyM-Krebs Partnering, SMART-NAFLD, DEEP-HCC network, Forschungsnetzwerk LiSyM-Krebs
Institutions: Universität Leipzig - Medizinische Fakultät - Institut für Biochemie, Universität Leipzig - Sächsischer Inkubator für Klinische Translation (SIKT)
Group leader of the junior group: The Hedgehog Signalling Pathway (LiSyM-JGMMS)
Liver Systems Medicine : striving to develop non-invasive methods for diagnosing and treating NAFLD by combining mathematical modeling and biological research. LiSyM, is a multidisciplinary research network, in which molecular and cell biologists, clinical researchers, pharmacologists and experts in mathematical modeling examine the liver in its entirety. LiSyM research focuses on the metabolic liver disease non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis ...
Projects: LiSyM Core Infrastructure and Management (LiSyM-PD), LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI), LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi), Model Guided Pharmacotherapy In Chronic Liver Disease (LiSyM-MGP), Molecular Steatosis - Imaging & Modeling (LiSyM-MSIM), The Hedgehog Signalling Pathway (LiSyM-JGMMS), Multi-Scale Models for Personalized Liver Function Tests (LiSyM-MM-PLF), LiSyM PALs, Project Management PTJ, LiSyM network, LiSyM Scientific Leadership Team (LiSyM-LT)
Web page: https://www.lisym.org/
One of the tasks of the healthy liver is to store fat. Yet, at some stage, too much fat makes the liver sick. One critical time point occurs when a healthy fatty liver becomes inflamed and progresses to steatohepatitis, or NASH. LiSyM-Pillar I will identify what events lead to this transition. Does it occur in all parts of the liver? Which molecules indicate that it is taking place? Can the degeneration be stopped or undone - and if so, how?
Programme: LiSyM: Liver Systems Medicine
Public web page: http://www.lisym.org/our-work/pillar-research/zones-of-the-liver
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Hepatocytes captured by laser microdissection were obtained from three hepatic zones (pericentral, intermediate and periportal) and subjected to reduced representation bisulfite sequencing and RNA-seq resulting in 114 ...
Submitter: Mario Brosch
Investigation: Epigenomic analysis of micro-dissected human liver
Assays: DNA-methylation at binding sites of uniformly expressed transcription fa..., DNA-methylation at binding sites of uniformly expressed transcription fa..., DNA-methylation at binding sites of uniformly expressed transcription fa..., Transcriptomic analysis of hepatocytes ( hepatic zone: intermediate (IZ), Transcriptomic analysis of hepatocytes ( hepatic zone: periportal (PP), Transcriptomic analysis of hepatocytes ; hepatic zone: pericentral (CV)
Transcriptomic analysis of hepatocytes captured by laser micro-dissection from hepatic zone: pericentral (CV)
Submitter: Mario Brosch
Assay type: RNA-seq Profiling
Technology type: Rna-seq
Investigation: Epigenomic analysis of micro-dissected human liver
DNA-methylation at binding sites of uniformly expressed transcription factors in human hepatocytes ; hepatic zone: pericentral (CV)
Submitter: Mario Brosch
Assay type: Methylation Profiling
Technology type: Technology Type
Investigation: Epigenomic analysis of micro-dissected human liver
Transcriptomic analysis of hepatocytes captured by laser micro-dissection from hepatic zone: intermediate (IZ)
Submitter: Mario Brosch
Assay type: RNA-seq Profiling
Technology type: Rna-seq
Investigation: Epigenomic analysis of micro-dissected human liver
Transcriptomic analysis of hepatocytes captured by laser micro-dissection from hepatic zone: periportal (PP)
Submitter: Mario Brosch
Assay type: RNA-seq Profiling
Technology type: Rna-seq
Investigation: Epigenomic analysis of micro-dissected human liver
DNA-methylation at binding sites of uniformly expressed transcription factors in human hepatocytes ; hepatic zone: intermediate (IZ)
Submitter: Olga Krebs
Assay type: Methylation Profiling
Technology type: Technology Type
Investigation: Epigenomic analysis of micro-dissected human liver
Human RNA-Seq data set GSM2819712 stored in NCBI (GEO)
Creator: Mario Brosch
Submitter: Mario Brosch
External LinkHuman RNA-Seq data set GSM2819698 stored in NCBI (GEO)
liver tissue sample : 6922_IZ_RNA
Creator: Mario Brosch
Submitter: Mario Brosch
Human RNA-Seq data set GSM2819714 stored in NCBI (GEO)
Creator: Mario Brosch
Submitter: Mario Brosch
Human RNA-Seq data set GSM2819713 stored in NCBI (GEO)
Creator: Mario Brosch
Submitter: Mario Brosch
Human RNA-Seq data set GSM2819711 stored in NCBI (GEO)
Creator: Mario Brosch
Submitter: Mario Brosch
SOP : liver tissue microdissection for RNA sequencing
Creator: Mario Brosch
Submitter: Mario Brosch
Abstract (Expand)
Authors: Mario Brosch, Kathrin Kattler, Alexander Herrmann, Witigo von Schönfels, Karl Nordström, Daniel Seehofer, Georg Damm, Thomas Becker, Sebastian Zeissig, Sophie Nehring, Fabian Reichel, Vincent Moser, Raghavan Veera Thangapandi, Felix Stickel, Gustavo Baretton, Christoph Röcken, Michael Muders, Madlen Matz-Soja, Michael Krawczak, Gilles Gasparoni, Hella Hartmann, Andreas Dahl, Clemens Schafmayer, Jörn Walter, Jochen Hampe
Date Published: 1st Dec 2018
Publication Type: Not specified
