Publications

@article{nokey,

title = {Data report on gene expression after hepatic portal vein ligation (PVL) in rats},

author = {Daria Meyer and Joanna Kosacka and Martin von Bergen and Bruno Christ and Manja Marz},

doi = {10.3389/fgene.2024.1421955},

year  = {2024},

date = {2024-08-21},

journal = {Front Genet},

volume = {15},

pages = {1421955},

keywords = {liver, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Christ2021,

title = {Hepatectomy-Induced Alterations in Hepatic Perfusion and Function - Toward Multi-Scale Computational Modeling for a Better Prediction of Post-hepatectomy Liver Function},

author = {Bruno Christ and Maximilian Collatz and Uta Dahmen and Karl-Heinz Herrmann and Sebastian Höpfl and Matthias König and Lena Lambers and Manja Marz and Daria Meyer and Nicole Radde and Jürgen R. Reichenbach and Tim Ricken and Hans-Michael Tautenhahn},

doi = {10.3389/fphys.2021.733868},

year  = {2021},

date = {2021-11-18},

urldate = {2021-11-18},

journal = {Front Physiol},

volume = {12},

pages = {733868},

abstract = {Liver resection causes marked perfusion alterations in the liver remnant both on the organ scale (vascular anatomy) and on the microscale (sinusoidal blood flow on tissue level). These changes in perfusion affect hepatic functions via direct alterations in blood supply and drainage, followed by indirect changes of biomechanical tissue properties and cellular function. Changes in blood flow impose compression, tension and shear forces on the liver tissue. These forces are perceived by mechanosensors on parenchymal and non-parenchymal cells of the liver and regulate cell-cell and cell-matrix interactions as well as cellular signaling and metabolism. These interactions are key players in tissue growth and remodeling, a prerequisite to restore tissue function after PHx. Their dysregulation is associated with metabolic impairment of the liver eventually leading to liver failure, a serious post-hepatectomy complication with high morbidity and mortality. Though certain links are known, the overall functional change after liver surgery is not understood due to complex feedback loops, non-linearities, spatial heterogeneities and different time-scales of events. Computational modeling is a unique approach to gain a better understanding of complex biomedical systems. This approach allows (i) integration of heterogeneous data and knowledge on multiple scales into a consistent view of how perfusion is related to hepatic function; (ii) testing and generating hypotheses based on predictive models, which must be validated experimentally and clinically. In the long term, computational modeling will (iii) support surgical planning by predicting surgery-induced perfusion perturbations and their functional (metabolic) consequences; and thereby (iv) allow minimizing surgical risks for the individual patient. Here, we review the alterations of hepatic perfusion, biomechanical properties and function associated with hepatectomy. Specifically, we provide an overview over the clinical problem, preoperative diagnostics, functional imaging approaches, experimental approaches in animal models, mechanoperception in the liver and impact on cellular metabolism, omics approaches with a focus on transcriptomics, data integration and uncertainty analysis, and computational modeling on multiple scales. Finally, we provide a perspective on how multi-scale computational models, which couple perfusion changes to hepatic function, could become part of clinical workflows to predict and optimize patient outcome after complex liver surgery.},

keywords = {liver, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Gerresheim:20,

title = {Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication},

author = {Gesche K. Gerresheim and Carolin S. Hess and Lyudmila A. Shalamova and Markus Fricke and Manja Marz and Dmitri E. Andreev and Ivan N. Shatsky and Michael Niepmann},

doi = {10.3390/ijms21186955},

year  = {2020},

date = {2020-09-22},

urldate = {2020-09-22},

journal = {Int J Mol Sci},

volume = {21},

number = {18},

pages = {6955},

publisher = {MDPI AG},

abstract = {Hepatitis C virus (HCV) infects liver cells and often causes chronic infection, also leading to liver cirrhosis and cancer. In the cytoplasm, the viral structural and non-structural (NS) proteins are directly translated from the plus strand HCV RNA genome. The viral proteins NS3 to NS5B proteins constitute the replication complex that is required for RNA genome replication via a minus strand antigenome. The most C-terminal protein in the genome is the NS5B replicase, which needs to initiate antigenome RNA synthesis at the very 3′-end of the plus strand. Using ribosome profiling of cells replicating full-length infectious HCV genomes, we uncovered that ribosomes accumulate at the HCV stop codon and about 30 nucleotides upstream of it. This pausing is due to the presence of conserved rare, inefficient Wobble codons upstream of the termination site. Synonymous substitution of these inefficient codons to efficient codons has negative consequences for viral RNA replication but not for viral protein synthesis. This pausing may allow the enzymatically active replicase core to find its genuine RNA template in cis, while the protein is still held in place by being stuck with its C-terminus in the exit tunnel of the paused ribosome.

},

keywords = {cancer, liver, ncRNAs, RNA structure, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Srivastava:20,

title = {Tissue-specific Gene Expression Changes Are Associated with Aging in Mice},

author = {Akash Srivastava and Emanuel Barth and Maria A. Ermolaeva and Madlen Guenther and Christiane Frahm and Manja Marz and Otto W. Witte},

doi = {10.1016/j.gpb.2020.12.001},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Genomics Proteomics Bioinformatics},

volume = {18},

number = {4},

pages = {430--442},

publisher = {Elsevier BV},

abstract = {Aging is a complex process that can be characterized by functional and cognitive decline in an individual. Aging can be assessed based on the functional capacity of vital organs and their intricate interactions with one another. Thus, the nature of aging can be described by focusing on a specific organ and an individual itself. However, to fully understand the complexity of aging, one must investigate not only a single tissue or biological process but also its complex interplay and interdependencies with other biological processes. Here, using RNA-seq, we monitored changes in the transcriptome during aging in four tissues (including brain, blood, skin and liver) in mice at 9 months, 15 months, and 24 months, with a final evaluation at the very old age of 30 months. We identified several genes and processes that were differentially regulated during aging in both tissue-dependent and tissue-independent manners. Most importantly, we found that the electron transport chain (ETC) of mitochondria was similarly affected at the transcriptome level in the four tissues during the aging process. We also identified the liver as the tissue showing the largest variety of differentially expressed genes (DEGs) over time. Lcn2 (Lipocalin-2) was found to be similarly regulated among all tissues, and its effect on longevity and survival was validated using its orthologue in Caenorhabditis elegans. Our study demonstrated that the molecular processes of aging are relatively subtle in their progress, and the aging process of every tissue depends on the tissue’s specialized function and environment. Hence, individual gene or process alone cannot be described as the key of aging in the whole organism.},

keywords = {aging, differential expression analysis, liver, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Gerresheim:19,

title = {Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling},

author = {Gesche Gerresheim and Jochen Bathke and Audrey Michel and Dmitri E. Andreev and Lyudmila Shalamova and Oliver Rossbach and Pan Hu and Dieter Glebe and Markus Fricke and Manja Marz and Alexander Goesmann and Stephen Kiniry and Pavel Baranov and Ivan Shatsky and Michael Niepmann},

doi = {10.3390/ijms20061321},

year  = {2019},

date = {2019-03-15},

urldate = {2019-03-15},

journal = {Int J Mol Sci},

volume = {20},

number = {6},

pages = {1321},

publisher = {MDPI AG},

abstract = {Background: Hepatitis C virus (HCV) infects human liver hepatocytes, often leading to liver cirrhosis and hepatocellular carcinoma (HCC). It is believed that chronic infection alters host gene expression and favors HCC development. In particular, HCV replication in Endoplasmic Reticulum (ER) derived membranes induces chronic ER stress. How HCV replication affects host mRNA translation and transcription at a genome wide level is not yet known. Methods: We used Riboseq (Ribosome Profiling) to analyze transcriptome and translatome changes in the Huh-7.5 hepatocarcinoma cell line replicating HCV for 6 days. Results: Established viral replication does not cause global changes in host gene expression—only around 30 genes are significantly differentially expressed. Upregulated genes are related to ER stress and HCV replication, and several regulated genes are known to be involved in HCC development. Some mRNAs (PPP1R15A/GADD34, DDIT3/CHOP, and TRIB3) may be subject to upstream open reading frame (uORF) mediated translation control. Transcriptional downregulation mainly affects mitochondrial respiratory chain complex core subunit genes. Conclusion: After establishing HCV replication, the lack of global changes in cellular gene expression indicates an adaptation to chronic infection, while the downregulation of mitochondrial respiratory chain genes indicates how a virus may further contribute to cancer cell-like metabolic reprogramming (“Warburg effect”) even in the hepatocellular carcinoma cells used here. },

keywords = {cancer, differential expression analysis, liver, RNA structure, virus host interaction, viruses},

pubstate = {published},

tppubtype = {article}

}

@article{Barth:19,

title = {Conserved aging-related signatures of senescence and inflammation in different tissues and species.},

author = {Emanuel Barth and Akash Srivastava and Milan Stojiljkovic and Christiane Frahm and Hubertus Axer and Otto W Witte and Manja Marz},

doi = {10.18632/aging.102345},

year  = {2019},

date = {2019-02-26},

urldate = {2019-02-26},

journal = {Aging},

volume = {11},

number = {19},

pages = {8556—8572},

abstract = {Increasing evidence indicates that chronic inflammation and senescence are the cause of many severe age-related diseases, with both biological processes highly upregulated during aging. However, until now, it has remained unknown whether specific inflammation- or senescence-related genes exist that are common between different species or tissues. These potential markers of aging could help to identify possible targets for therapeutic interventions of aging-associated afflictions and might also deepen our understanding of the principal mechanisms of aging. With the objective of identifying such signatures of aging and tissue-specific aging markers, we analyzed a multitude of cross-sectional RNA-Seq data from four evolutionarily distinct species (human, mouse and two fish) and four different tissues (blood, brain, liver and skin). In at least three different species and three different tissues, we identified several genes that displayed similar expression patterns that might serve as potential aging markers. Additionally, we show that genes involved in aging-related processes tend to be tighter controlled in long-lived than in average-lived individuals. These observations hint at a general genetic level that affect an individual's life span. Altogether, this descriptive study contributes to a better understanding of common aging signatures as well as tissue-specific aging patterns and supplies the basis for further investigative age-related studies.},

keywords = {aging, liver, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Morales-Prieto:18a,

title = {Peripheral blood exosomes pass blood-brain-barrier and induce glial cell activation},

author = {Diana M. Morales-Prieto and Milan Stojiljkovic and Celia Diezel and Priska-Elisabeth Streicher and Franziska Roestel and Julia Lindner and Sebastian Weis and Christian Schmeer and Manja Marz},

doi = {10.1101/471409},

year  = {2018},

date = {2018-11-29},

urldate = {2018-11-29},

journal = {bioRxiv},

pages = {471409},

publisher = {Cold Spring Harbor Laboratory},

abstract = {Background Exosomes are involved in intracellular communication and contain proteins, mRNAs, miRNAs, and signaling molecules. Exosomes were shown to act as neuroinflammatory mediators involved in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS). Brain aging has been associated to increased neuroinflammation. In addition, a decreased extracellular vesicle concentration was observed in aging tissues. The specific mechanisms how exosomes and aging are connected are not known yet.



Results Here we have shown that peripheral injection had almost no effect on selected gene expression in the liver. However, exosome injection has led to changes in the specific markers of glial cell activation (CD68, Iba1, GFAP). Interestingly, only injection of exosomes isolated from aged mice induced significant activation of astrocyte cells, as shown by increased GFAP expression.



Conclusion Transcription levels of genes GFAP, TGF-β, CD68, Iba1 known to be involved in glial cell function are significantly changing after introduction of peripheral extracellular vesicles. Exosomes were able to pass blood brain barrier and induce glial cell activation. GFAP known to be a specific astrocyte activation marker was significantly higher expressed after injection of old but not young exosomes, indicating a possible role of exosomes in the mechanisms of brain aging.},

keywords = {aging, extracellular vesicles, liver, ncRNAs},

pubstate = {published},

tppubtype = {article}

}

@article{Gerresheim:17,

title = {microRNA-122 target sites in the hepatitis C virus RNA NS5B coding region and 3' untranslated region: function in replication and influence of RNA secondary structure},

author = {Gesche K Gerresheim and Nadia Dünnes and Anika Nieder-Röhrmann and Lyudmila A Shalamova and Markus Fricke and Ivo Hofacker and Christian {Höner zu Siederdissen} and Manja Marz and Michael Niepmann},

doi = {10.1007/s00018-016-2377-9},

year  = {2016},

date = {2016-09-27},

urldate = {2016-09-27},

journal = {Cell Mol Life Sci},

volume = {74},

pages = {747--760},

abstract = {We have analyzed the binding of the liver-specific microRNA-122 (miR-122) to three conserved target sites of hepatitis C virus (HCV) RNA, two in the non-structural protein 5B (NS5B) coding region and one in the 3' untranslated region (3'UTR). miR-122 binding efficiency strongly depends on target site accessibility under conditions when the range of flanking sequences available for the formation of local RNA secondary structures changes. Our results indicate that the particular sequence feature that contributes most to the correlation between target site accessibility and binding strength varies between different target sites. This suggests that the dynamics of miRNA/Ago2 binding not only depends on the target site itself but also on flanking sequence context to a considerable extent, in particular in a small viral genome in which strong selection constraints act on coding sequence and overlapping cis-signals and model the accessibility of cis-signals. In full-length genomes, single and combination mutations in the miR-122 target sites reveal that site 5B.2 is positively involved in regulating overall genome replication efficiency, whereas mutation of site 5B.3 showed a weaker effect. Mutation of the 3'UTR site and double or triple mutants showed no significant overall effect on genome replication, whereas in a translation reporter RNA, the 3'UTR target site inhibits translation directed by the HCV 5'UTR. Thus, the miR-122 target sites in the 3'-region of the HCV genome are involved in a complex interplay in regulating different steps of the HCV replication cycle.},

keywords = {liver, ncRNAs, RNA / transcriptomics, RNA structure, viruses},

pubstate = {published},

tppubtype = {article}

}