@article {125, title = {Multiomic atlas with functional stratification and developmental dynamics of zebrafish cis-regulatory elements.}, journal = {Nat Genet}, volume = {54}, year = {2022}, month = {2022 Jul}, pages = {1037-1050}, abstract = {

Zebrafish, a popular organism for studying embryonic development and for modeling human diseases, has so far lacked a systematic functional annotation program akin to those in other animal models. To address this, we formed the international DANIO-CODE consortium and created a central repository to store and process zebrafish developmental functional genomic data. Our data coordination center ( https://danio-code.zfin.org ) combines a total of 1,802 sets of unpublished and re-analyzed published genomic data, which we used to improve existing annotations and show its utility in experimental design. We identified over 140,000 cis-regulatory elements throughout development, including classes with distinct features dependent on their activity in time and space. We delineated the distinct distance topology and chromatin features between regulatory elements active during zygotic genome activation and those active during organogenesis. Finally, we matched regulatory elements and epigenomic landscapes between zebrafish and mouse and predicted functional relationships between them beyond sequence similarity, thus extending the utility of zebrafish developmental genomics to mammals.

}, keywords = {Animals, Chromatin, Databases, Genetic, Gene Expression Regulation, Developmental, Genome, Genomics, Humans, Mice, Molecular Sequence Annotation, Organogenesis, Regulatory Sequences, Nucleic Acid, Zebrafish, Zebrafish Proteins}, issn = {1546-1718}, doi = {10.1038/s41588-022-01089-w}, author = {Baranasic, Damir and H{\"o}rtenhuber, Matthias and Balwierz, Piotr J and Zehnder, Tobias and Mukarram, Abdul Kadir and Nepal, Chirag and V{\'a}rnai, Csilla and Hadzhiev, Yavor and Jimenez-Gonzalez, Ada and Li, Nan and Wragg, Joseph and D{\textquoteright}Orazio, Fabio M and Relic, Dorde and Pachkov, Mikhail and D{\'\i}az, Noelia and Hern{\'a}ndez-Rodr{\'\i}guez, Benjam{\'\i}n and Chen, Zelin and Stoiber, Marcus and Dong, Micha{\"e}l and Stevens, Irene and Ross, Samuel E and Eagle, Anne and Martin, Ryan and Obasaju, Oluwapelumi and Rastegar, Sepand and McGarvey, Alison C and Kopp, Wolfgang and Chambers, Emily and Wang, Dennis and Kim, Hyejeong R and Acemel, Rafael D and Naranjo, Silvia and {\L}api{\'n}ski, Maciej and Chong, Vanessa and Mathavan, Sinnakaruppan and Peers, Bernard and Sauka-Spengler, Tatjana and Vingron, Martin and Carninci, Piero and Ohler, Uwe and Lacadie, Scott Allen and Burgess, Shawn M and Winata, Cecilia and van Eeden, Freek and Vaquerizas, Juan M and G{\'o}mez-Skarmeta, Jos{\'e} Luis and Onichtchouk, Daria and Brown, Ben James and Bogdanovic, Ozren and van Nimwegen, Erik and Westerfield, Monte and Wardle, Fiona C and Daub, Carsten O and Lenhard, Boris and M{\"u}ller, Ferenc} } @article {122, title = {Multi-omics analyses of early liver injury reveals cell-type-specific transcriptional and epigenomic shift.}, journal = {BMC Genomics}, volume = {22}, year = {2021}, month = {2021 Dec 18}, pages = {904}, 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.

}, keywords = {Animals, Endothelial Cells, Epigenomics, Liver, Zebrafish}, issn = {1471-2164}, doi = {10.1186/s12864-021-08173-1}, author = {Migda{\l}, Maciej and Tralle, Eugeniusz and Nahia, Karim Abu and Bugajski, {\L}ukasz and K{\k e}dzierska, Katarzyna Zofia and Garbicz, Filip and Piwocka, Katarzyna and Winata, Cecilia Lanny and Pawlak, Micha{\l}} } @article {70, title = {Mercury-induced hepatotoxicity in zebrafish: in vivo mechanistic insights from transcriptome analysis, phenotype anchoring and targeted gene expression validation.}, journal = {BMC Genomics}, volume = {11}, year = {2010}, month = {2010}, pages = {212}, abstract = {

BACKGROUND: Mercury is a prominent environmental contaminant that causes detrimental effects to human health. Although the liver has been known to be a main target organ, there is limited information on in vivo molecular mechanism of mercury-induced toxicity in the liver. By using transcriptome analysis, phenotypic anchoring and validation of targeted gene expression in zebrafish, mercury-induced hepatotoxicity was investigated and a number of perturbed cellular processes were identified and compared with those captured in the in vitro human cell line studies.

RESULTS: Hepato-transcriptome analysis of mercury-exposed zebrafish revealed that the earliest deregulated genes were associated with electron transport chain, mitochondrial fatty acid beta-oxidation, nuclear receptor signaling and apoptotic pathway, followed by complement system and proteasome pathway, and thereafter DNA damage, hypoxia, Wnt signaling, fatty acid synthesis, gluconeogenesis, cell cycle and motility. Comparative meta-analysis of microarray data between zebrafish liver and human HepG2 cells exposed to mercury identified some common toxicological effects of mercury-induced hepatotoxicity in both models. Histological analyses of liver from mercury-exposed fish revealed morphological changes of liver parenchyma, decreased nucleated cell count, increased lipid vesicles, glycogen and apoptotic bodies, thus providing phenotypic evidence for anchoring of the transcriptome analysis. Validation of targeted gene expression confirmed deregulated gene-pathways from enrichment analysis. Some of these genes responding to low concentrations of mercury may serve as toxicogenomic-based markers for detection and health risk assessment of environmental mercury contaminations.

CONCLUSION: Mercury-induced hepatotoxicity was triggered by oxidative stresses, intrinsic apoptotic pathway, deregulation of nuclear receptor and kinase activities including Gsk3 that deregulates Wnt signaling pathway, gluconeogenesis, and adipogenesis, leading to mitochondrial dysfunction, endocrine disruption and metabolic disorders. This study provides important mechanistic insights into mercury-induced liver toxicity in a whole-animal physiology context, which will help in understanding the syndromes caused by mercury poisoning. The molecular conservation of mercury-induced hepatotoxicity between zebrafish and human cell line reveals the feasibility of using zebrafish to model molecular toxicity in human for toxicant risk assessments.

}, keywords = {Animals, Apoptosis, Arsenic, Cell Adhesion, Cell Line, Gene Expression Profiling, Hepatocytes, Humans, Liver, Mercury, Oligonucleotide Array Sequence Analysis, Zebrafish}, issn = {1471-2164}, doi = {10.1186/1471-2164-11-212}, author = {Ung, Choong Yong and Lam, Siew Hong and Hlaing, Mya Myintzu and Winata, Cecilia L and Korzh, Svetlana and Mathavan, Sinnakaruppan and Gong, Zhiyuan} }