@article {127, title = {xcore: an R package for inference of gene expression regulators.}, journal = {BMC Bioinformatics}, volume = {24}, year = {2023}, month = {2023 Jan 11}, pages = {14}, abstract = {

BACKGROUND: Elucidating the Transcription Factors (TFs) that drive the gene expression changes in a given experiment is a common question asked by researchers. The existing methods rely on the predicted Transcription Factor Binding Site (TFBS) to model the changes in the motif activity. Such methods only work for TFs that have a motif and assume the TF binding profile is the same in all cell types.

RESULTS: Given the wealth of the ChIP-seq data available for a wide range of the TFs in various cell types, we propose that gene expression modeling can be done using ChIP-seq "signatures" directly, effectively skipping the motif finding and TFBS prediction steps. We present xcore, an R package that allows TF activity modeling based on ChIP-seq signatures and the user{\textquoteright}s gene expression data. We also provide xcoredata a companion data package that provides a collection of preprocessed ChIP-seq signatures. We demonstrate that xcore leads to biologically relevant predictions using transforming growth factor beta induced epithelial-mesenchymal transition time-courses, rinderpest infection time-courses, and embryonic stem cells differentiated to cardiomyocytes time-course profiled with Cap Analysis Gene Expression.

CONCLUSIONS: xcore provides a simple analytical framework for gene expression modeling using linear models that can be easily incorporated into differential expression analysis pipelines. Taking advantage of public ChIP-seq databases, xcore can identify meaningful molecular signatures and relevant ChIP-seq experiments.

}, keywords = {Animals, Binding Sites, Chromatin Immunoprecipitation, Chromatin Immunoprecipitation Sequencing, Gene Expression, Protein Binding, Transcription Factors}, issn = {1471-2105}, doi = {10.1186/s12859-022-05084-0}, author = {Migda{\l}, Maciej and Arakawa, Takahiro and Takizawa, Satoshi and Furuno, Masaaki and Suzuki, Harukazu and Arner, Erik and Winata, Cecilia Lanny and Kaczkowski, Bogumi{\l}} } @article {124, title = {Adar-mediated A-to-I editing is required for embryonic patterning and innate immune response regulation in zebrafish.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 Sep 20}, pages = {5520}, abstract = {

Adenosine deaminases (ADARs) catalyze the deamination of adenosine to inosine, also known as A-to-I editing, in RNA. Although A-to-I editing occurs widely across animals and is well studied, new biological roles are still being discovered. Here, we study the role of A-to-I editing in early zebrafish development. We demonstrate that Adar, the zebrafish orthologue of mammalian ADAR1, is essential for establishing the antero-posterior and dorso-ventral axes and patterning. Genome-wide editing discovery reveals pervasive editing in maternal and the earliest zygotic transcripts, the majority of which occurred in the 3{\textquoteright}-UTR. Interestingly, transcripts implicated in gastrulation as well as dorso-ventral and antero-posterior patterning are found to contain multiple editing sites. Adar knockdown or overexpression affect gene expression by 12 hpf. Analysis of adar-/- zygotic mutants further reveals that the previously described role of Adar in mammals in regulating the innate immune response is conserved in zebrafish. Our study therefore establishes distinct maternal and zygotic functions of RNA editing by Adar in embryonic patterning along the zebrafish antero-posterior and dorso-ventral axes, and in the regulation of the\ innate immune response, respectively.

}, keywords = {Adenosine, Animals, Immunity, Innate, Inosine, Mammals, RNA, RNA-Binding Proteins, Zebrafish}, issn = {2041-1723}, doi = {10.1038/s41467-022-33260-6}, author = {Niescierowicz, Katarzyna and Pryszcz, Leszek and Navarrete, Cristina and Tralle, Eugeniusz and Sulej, Agata and Abu Nahia, Karim and Kasprzyk, Marta El{\.z}bieta and Misztal, Katarzyna and Pateria, Abhishek and Paku{\l}a, Adrianna and Bochtler, Matthias and Winata, Cecilia} } @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 {115, title = {Targeted RNA Knockdown by a Type III CRISPR-Cas Complex in Zebrafish.}, journal = {CRISPR J}, volume = {3}, year = {2020}, month = {2020 08}, pages = {299-313}, abstract = {

RNA interference is a powerful experimental tool for RNA knockdown, but not all organisms are amenable. Here, we provide a proof of principle demonstration that a type III Csm effector complex can be used for programmable mRNA transcript degradation in eukaryotes. In zebrafish, Csm complex (StCsm) proved effective for knockdown of maternally expressed in germ cells of fish. It also led to significant, albeit less drastic, fluorescence reduction at one day postfertilization in and ( fish that express zygotically. StCsm targeted against the endogenous elicited the characteristic one-eyed phenotype with greater than 50\% penetrance, and hence with similar efficiency to morpholino-mediated knockdown. We conclude that Csm-mediated knockdown is very efficient for maternal transcripts and can also be used for mixed maternal/early zygotic and early zygotic transcripts, in some cases reaching comparable efficiency to morpholino-based knockdown without significant off-target effects.

}, issn = {2573-1602}, doi = {10.1089/crispr.2020.0032}, author = {Fricke, Thomas and Smalakyte, Dalia and Lapinski, Maciej and Pateria, Abhishek and Weige, Charles and Pastor, Michal and Kolano, Agnieszka and Winata, Cecilia and Siksnys, Virginijus and Tamulaitis, Gintautas and Bochtler, Matthias} } @article {pmid29229769, title = {Cytoplasmic polyadenylation-mediated translational control of maternal mRNAs directs maternal-to-zygotic transition}, journal = {Development}, volume = {145}, year = {2018}, month = {01/2018}, abstract = {

In the earliest stages of animal development following fertilization, maternally deposited mRNAs direct biological processes to the point of zygotic genome activation (ZGA). These maternal mRNAs undergo cytoplasmic polyadenylation (CPA), suggesting translational control of their activation. To elucidate the biological role of CPA during embryogenesis, we performed genome-wide polysome profiling at several stages of zebrafish development. Our analysis revealed a correlation between CPA and polysome-association dynamics, demonstrating a coupling of translation to the CPA of maternal mRNAs. Pan-embryonic CPA inhibition disrupted the maternal-to-zygotic transition (MZT), causing a failure of developmental progression beyond the mid-blastula transition and changes in global gene expression that indicated a failure of ZGA and maternal mRNA clearance. Among the genes that were differentially expressed were those encoding chromatin modifiers and key transcription factors involved in ZGA, including nanog, pou5f3 and sox19b, which have distinct CPA dynamics. Our results establish the necessity of CPA for ensuring progression of the MZT. The RNA-seq data generated in this study represent a valuable zebrafish resource for the discovery of novel elements of the early embryonic transcriptome.

}, author = {Winata, C. L. and {\L}api{\'n}ski, M. and Pryszcz, L. and Vaz, C. and Bin Ismail, M. H. and Nama, S. and Hajan, H. S. and Lee, S. G. P. and Korzh, V. and Sampath, P. and Tanavde, V. and Mathavan, S.} } @article {75, title = {DANIO-CODE: Toward an Encyclopedia of DNA Elements in Zebrafish.}, journal = {Zebrafish}, volume = {13}, year = {2016}, month = {2016 Feb}, pages = {54-60}, abstract = {

The zebrafish has emerged as a model organism for genomics studies. The symposium "Toward an encyclopedia of DNA elements in zebrafish" held in London in December 2014, was coorganized by Ferenc M{\"u}ller and Fiona Wardle. This meeting is a follow-up of a similar previous workshop held 2 years earlier and represents a push toward the formalization of a community effort to annotate functional elements in the zebrafish genome. The meeting brought together zebrafish researchers, bioinformaticians, as well as members of established consortia, to exchange scientific findings and experience, as well as to discuss the initial steps toward the formation of a DANIO-CODE consortium. In this study, we provide the latest updates on the current progress of the consortium{\textquoteright}s efforts, opening up a broad invitation to researchers to join in and contribute to DANIO-CODE.

}, keywords = {ZDGaffiliated}, issn = {1557-8542}, doi = {10.1089/zeb.2015.1179}, author = {Tan, Haihan and Onichtchouk, Daria and Winata, Cecilia} } @article {74, title = {Impaired development of neural-crest cell-derived organs and intellectual disability caused by MED13L haploinsufficiency.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Nov}, pages = {1311-20}, abstract = {

MED13L is a component subunit of the Mediator complex, an important regulator of transcription that is highly conserved across eukaryotes. Here, we report MED13L disruption in a translocation t(12;19) breakpoint of a patient with Pierre-Robin syndrome, moderate intellectual disability, craniofacial anomalies, and muscular defects. The phenotype is similar to previously described patients with MED13L haploinsufficiency. Knockdown of MED13L orthologue in zebrafish, med13b, showed early defective migration of cranial neural crest cells (NCCs) that contributed to cartilage structure deformities in the later stage, recapitulating craniofacial anomalies seen in human patients. Notably, we observed abnormal distribution of developing neurons in different brain regions of med13b morphant embryos, which could be rescued upon introduction of full-length human MED13L mRNA. To compare with mammalian system, we suppressed MED13L expression by short-hairpin RNA in ES-derived human neural progenitors, and differentiated them into neurons. Transcriptome analysis revealed differential expression of components of Wnt and FGF signaling pathways in MED13L-deficient neurons. Our finding provides a novel insight into the mechanism of overlapping phenotypic outcome targeting NCCs derivatives organs in patients with MED13L haploinsufficiency, and emphasizes a clinically recognizable syndromic phenotype in these patients.

}, keywords = {Animals, Cell Differentiation, Cell Movement, Child, Preschool, Chromosome Breakpoints, Disease Models, Animal, Embryonic Stem Cells, Female, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Genetic Association Studies, Haploinsufficiency, Humans, Intellectual Disability, Mediator Complex, Neural Crest, Neurons, Phenotype, RNA, Messenger, Sequence Analysis, DNA, Transcriptome, Translocation, Genetic, Zebrafish}, issn = {1098-1004}, doi = {10.1002/humu.22636}, author = {Utami, Kagistia Hana and Winata, Cecilia L and Hillmer, Axel M and Aksoy, Irene and Long, Hoang Truong and Liany, Herty and Chew, Elaine G Y and Mathavan, Sinnakaruppan and Tay, Stacey K H and Korzh, Vladimir and Sarda, Pierre and Davila, Sonia and Cacheux, Valere} } @article {65, title = {Transcriptome kinetics of arsenic-induced adaptive response in zebrafish liver.}, journal = {Physiol Genomics}, volume = {27}, year = {2006}, month = {2006 Nov 27}, pages = {351-61}, abstract = {

Arsenic is a prominent environmental toxicant and carcinogen; however, its molecular mechanism of toxicity and carcinogenicity remains poorly understood. In this study, we performed microarray-based expression profiling on liver of zebrafish exposed to 15 parts/million (ppm) arsenic [As(V)] for 8-96 h to identify global transcriptional changes and biological networks involved in arsenic-induced adaptive responses in vivo. We found that there was an increase of transcriptional activity associated with metabolism, especially for biosyntheses, membrane transporter activities, cytoplasm, and endoplasmic reticulum in the 96 h of arsenic treatment, while transcriptional programs for proteins in catabolism, energy derivation, and stress response remained active throughout the arsenic treatment. Many differentially expressed genes encoding proteins involved in heat shock proteins, DNA damage/repair, antioxidant activity, hypoxia induction, iron homeostasis, arsenic metabolism, and ubiquitin-dependent protein degradation were identified, suggesting strongly that DNA and protein damage as a result of arsenic metabolism and oxidative stress caused major cellular injury. These findings were comparable with those reported in mammalian systems, suggesting that the zebrafish liver coupled with the available microarray technology present an excellent in vivo toxicogenomic model for investigating arsenic toxicity. We proposed an in vivo, acute arsenic-induced adaptive response model of the zebrafish liver illustrating the relevance of many transcriptional activities that provide both global and specific information of a coordinated adaptive response to arsenic in the liver.

}, keywords = {Adaptation, Physiological, Animals, Arsenic, Down-Regulation, Gene Expression Profiling, Gene Expression Regulation, Genomics, Liver, Male, Metabolic Networks and Pathways, Oligonucleotide Array Sequence Analysis, Transcription, Genetic, Up-Regulation, Zebrafish}, issn = {1531-2267}, doi = {10.1152/physiolgenomics.00201.2005}, author = {Lam, Siew Hong and Winata, Cecilia L and Tong, Yan and Korzh, Svetlana and Lim, Wen San and Korzh, Vladimir and Spitsbergen, Jan and Mathavan, Sinnakarupan and Miller, Lance D and Liu, Edison T and Gong, Zhiyuan} }