@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 Our data coordination center ( https://danio-code.zfin.org ) combines a total of 1,802 sets of unpublished and re-analyzed published genomic data, which we used to improve existing annotations and show its utility in experimental design.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 {119, title = {Cardiac-specific β-catenin deletion dysregulates energetic metabolism and mitochondrial function in perinatal cardiomyocytes.}, journal = {Mitochondrion}, volume = {60}, year = {2021}, month = {2021 09}, pages = {59-69}, abstract = {

β-Catenin signaling pathway regulates cardiomyocytes proliferation and differentiation, though its involvement in metabolic regulation of cardiomyocytes remains unknown. We used one-day-old mice with cardiac-specific knockout of β-catenin and neonatal rat ventricular myocytes treated with β-catenin inhibitor to investigate the role of β-catenin metabolism regulation in perinatal cardiomyocytes. Transcriptomics of perinatal β-catenin-ablated hearts revealed a dramatic shift in the expression of genes involved in metabolic processes. Further analysis indicated an inhibition of lipolysis and glycolysis in both in vitro and in vivo models. Finally, we showed that β-catenin deficiency leads to mitochondria dysfunction via the downregulation of Sirt1/PGC-1α pathway. We conclude that cardiac-specific β-catenin ablation disrupts the energy substrate shift that is essential for postnatal heart maturation, leading to perinatal lethality of homozygous β-catenin knockout mice.

}, issn = {1872-8278}, doi = {10.1016/j.mito.2021.07.005}, author = {Balatskyi, Volodymyr V and Vaskivskyi, Vasyl O and Myronova, Anna and Avramets, Diana and Nahia, Karim Abu and Macewicz, Larysa L and Ruban, Tetiana P and Kucherenko, Dar{\textquoteright}ya Yu and Soldatkin, Oleksandr O and Lushnikova, Iryna V and Skibo, Galyna G and Winata, Cecilia L and Dobrzyn, Pawel and Piven, Oksana O} } @article {112, title = {Dynamics of cardiomyocyte transcriptome and chromatin landscape demarcates key events of heart development.}, journal = {Genome Res}, volume = {29}, year = {2019}, month = {2019 03}, pages = {506-519}, abstract = {

Organogenesis involves dynamic regulation of gene transcription and complex multipathway interactions. Despite our knowledge of key factors regulating various steps of heart morphogenesis, considerable challenges in understanding its mechanism still exist because little is known about their downstream targets and interactive regulatory network. To better understand transcriptional regulatory mechanism driving heart development and the consequences of its disruption in vivo, we performed time-series analyses of the transcriptome and genome-wide chromatin accessibility in isolated cardiomyocytes (CMs) from wild-type zebrafish embryos at developmental stages corresponding to heart tube morphogenesis, looping, and maturation. We identified genetic regulatory modules driving crucial events of heart development that contained key cardiac TFs and are associated with open chromatin regions enriched for DNA sequence motifs belonging to the family of the corresponding TFs. Loss of function of cardiac TFs Gata5, Tbx5a, and Hand2 affected the cardiac regulatory networks and caused global changes in chromatin accessibility profile, indicating their role in heart development. Among regions with differential chromatin accessibility in mutants were highly conserved noncoding elements that represent putative enhancers driving heart development. The most prominent gene expression changes, which correlated with chromatin accessibility modifications within their proximal promoter regions, occurred between heart tube morphogenesis and looping, and were associated with metabolic shift and hematopoietic/cardiac fate switch during CM maturation. Our results revealed the dynamic regulatory landscape throughout heart development and identified interactive molecular networks driving key events of heart morphogenesis.

}, keywords = {Animals, Cells, Cultured, Chromatin, Chromatin Assembly and Disassembly, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Heart, Myocytes, Cardiac, Transcription Factors, Transcriptome, Zebrafish, Zebrafish Proteins}, issn = {1549-5469}, doi = {10.1101/gr.244491.118}, author = {Pawlak, Michal and Kedzierska, Katarzyna Z and Migdal, Maciej and Nahia, Karim Abu and Ramilowski, Jordan A and Bugajski, Lukasz and Hashimoto, Kosuke and Marconi, Aleksandra and Piwocka, Katarzyna and Carninci, Piero and Winata, Cecilia L} } @article {32, title = {Normalization of RNA-sequencing data from samples with varying mRNA levels.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e89158}, abstract = {

Methods for normalization of RNA-sequencing gene expression data commonly assume equal total expression between compared samples. In contrast, scenarios of global gene expression shifts are many and increasing. Here we compare the performance of three normalization methods when polyA(+) RNA content fluctuates significantly during zebrafish early developmental stages. As a benchmark we have used reverse transcription-quantitative PCR. The results show that reads per kilobase per million (RPKM) and trimmed mean of M-values (TMM) normalization systematically leads to biased gene expression estimates. Biological scaling normalization (BSN), designed to handle differences in total expression, showed improved accuracy compared to the two other methods in estimating transcript level dynamics. The results have implications for past and future studies using RNA-sequencing on samples with different levels of total or polyA(+) RNA.

}, keywords = {Animals, Base Sequence, Gene Expression, Gene Expression Profiling, Polymerase Chain Reaction, RNA, Messenger, Sequence Analysis, RNA, Zebrafish}, issn = {1932-6203}, doi = {10.1371/journal.pone.0089158}, author = {Aanes, H{\r a}vard and Winata, Cecilia L and Moen, Lars F and {\O}strup, Olga and Mathavan, Sinnakaruppan and Collas, Philippe and Rognes, Torbj{\o}rn and Alestr{\"o}m, Peter} } @article {33, title = {Genome wide analysis reveals Zic3 interaction with distal regulatory elements of stage specific developmental genes in zebrafish.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013 Oct}, pages = {e1003852}, abstract = {

Zic3 regulates early embryonic patterning in vertebrates. Loss of Zic3 function is known to disrupt gastrulation, left-right patterning, and neurogenesis. However, molecular events downstream of this transcription factor are poorly characterized. Here we use the zebrafish as a model to study the developmental role of Zic3 in vivo, by applying a combination of two powerful genomics approaches--ChIP-seq and microarray. Besides confirming direct regulation of previously implicated Zic3 targets of the Nodal and canonical Wnt pathways, analysis of gastrula stage embryos uncovered a number of novel candidate target genes, among which were members of the non-canonical Wnt pathway and the neural pre-pattern genes. A similar analysis in zic3-expressing cells obtained by FACS at segmentation stage revealed a dramatic shift in Zic3 binding site locations and identified an entirely distinct set of target genes associated with later developmental functions such as neural development. We demonstrate cis-regulation of several of these target genes by Zic3 using in vivo enhancer assay. Analysis of Zic3 binding sites revealed a distribution biased towards distal intergenic regions, indicative of a long distance regulatory mechanism; some of these binding sites are highly conserved during evolution and act as functional enhancers. This demonstrated that Zic3 regulation of developmental genes is achieved predominantly through long distance regulatory mechanism and revealed that developmental transitions could be accompanied by dramatic changes in regulatory landscape.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003852}, author = {Winata, Cecilia L and Kondrychyn, Igor and Kumar, Vibhor and Srinivasan, Kandhadayar G and Orlov, Yuriy and Ravishankar, Ashwini and Prabhakar, Shyam and Stanton, Lawrence W and Korzh, Vladimir and Mathavan, Sinnakaruppan} } @article {34, title = {Prepatterning of developmental gene expression by modified histones before zygotic genome activation.}, journal = {Dev Cell}, volume = {21}, year = {2011}, month = {2011 Dec 13}, pages = {993-1004}, abstract = {

A hallmark of anamniote vertebrate development is a window of embryonic transcription-independent cell divisions before onset of zygotic genome activation (ZGA). Chromatin determinants of ZGA are unexplored; however, marking of developmental genes by modified histones in sperm suggests a predictive role of histone marks for ZGA. In zebrafish, pre-ZGA development for ten cell cycles provides an opportunity to examine whether genomic enrichment in modified histones is present before initiation of transcription. By profiling histone H3 trimethylation on all zebrafish promoters before and after ZGA, we demonstrate here an epigenetic prepatterning of developmental gene expression. This involves pre-ZGA marking of transcriptionally inactive genes involved in homeostatic and developmental regulation by permissive H3K4me3 with or without repressive H3K9me3 or H3K27me3. Our data suggest that histone modifications are instructive for the developmental gene expression program.

}, keywords = {Animals, Body Patterning, Chromatin, Epigenesis, Genetic, Female, Gene Expression Regulation, Developmental, Histones, Male, Methylation, Multigene Family, Promoter Regions, Genetic, Spermatozoa, Zebrafish, Zebrafish Proteins}, issn = {1878-1551}, doi = {10.1016/j.devcel.2011.10.008}, author = {Lindeman, Leif C and Andersen, Ingrid S and Reiner, Andrew H and Li, Nan and Aanes, H{\r a}vard and {\O}strup, Olga and Winata, Cecilia L and Mathavan, Sinnakaruppan and M{\"u}ller, Ferenc and Alestr{\"o}m, Peter and Collas, Philippe} }