publications

2021

1. The Hippo pathway controls myofibril assembly and muscle fiber growth by regulating sarcomeric gene expression Kaya-Çopur, Aynur, Marchiano, Fabio, Hein, Marco Y, Alpern, Daniel, Russeil, Julie, Luis, Nuno Miguel, Mann, Matthias, Deplancke, Bart, and H Habermann, Frank Schnorrer eLife 2021 [Abs] [DOI]

   Skeletal muscles are composed of gigantic cells called muscle fibers, packed with force-producing myofibrils. During development the size of individual muscle fibers must dramatically enlarge to match with skeletal growth. How muscle growth is coordinated with growth of the contractile apparatus is not understood. Here, we use the large Drosophila flight muscles to mechanistically decipher how muscle fiber growth is controlled. We find that regulated activity of core members of the Hippo pathway is required to support flight muscle growth. Interestingly, we identify Dlg5 and Slmap as regulators of the STRIPAK phosphatase, which negatively regulates Hippo to enable post-mitotic muscle growth. Mechanistically, we show that the Hippo pathway controls timing and levels of sarcomeric gene expression during development and thus regulates the key components that physically mediate muscle growth. Since Dlg5, STRIPAK and the Hippo pathway are conserved a similar mechanism may contribute to muscle or cardiomyocyte growth in humans.

2. Prednisolone rescues Duchenne muscular dystrophy phenotypes in human pluripotent stem cell-derived skeletal muscle in vitro Tanoury, Ziad Al, Zimmerman, John F, Rao, Jyoti, Sieiro, Daniel, McNamara, Harold M, Cherrier, Thomas, Rodríguez-delaRosa, Alejandra, Hick-Colin, Aurore, Bousson, Fanny, Fugier-Schmucker, Charlotte, Marchiano, Fabio, Habermann, Bianca, Chal, Jérome, Nesmith, Alexander P, Gapon, Svetlana, Wagner, Erica, Gupta0, Vandana A, Bassel-Duby, Rhonda, Olson, Eric N, Cohen, Adam E, Parker, Kevin Kit, and Pourquié, Olivier PNAS 2021 [Abs] [DOI]

   Duchenne muscular dystrophy (DMD) is a devastating genetic disease leading to degeneration of skeletal muscles and premature death. How dystrophin absence leads to muscle wasting remains unclear. Here, we describe an optimized protocol to differentiate human induced pluripotent stem cells (iPSC) to a late myogenic stage. This allows us to recapitulate classical DMD phenotypes (mislocalization of proteins of the dystrophin-associated glycoprotein complex, increased fusion, myofiber branching, force contraction defects, and calcium hyperactivation) in isogenic DMD-mutant iPSC lines in vitro. Treatment of the myogenic cultures with prednisolone (the standard of care for DMD) can dramatically rescue force contraction, fusion, and branching defects in DMD iPSC lines. This argues that prednisolone acts directly on myofibers, challenging the largely prevalent view that its beneficial effects are caused by antiinflammatory properties. Our work introduces a human in vitro model to study the onset of DMD pathology and test novel therapeutic approaches.

3. AnnoMiner is a new web-tool to integrate epigenetics, transcription factor occupancy and transcriptomics data to predict transcriptional regulators Meiler, Arno, Marchiano, Fabio, Haering, Margaux, Weitkunat, Manuela, Schnorrer, Frank, and Habermann, Bianca H. ScientificReports 2021 [Abs] [DOI]

   Gene expression regulation requires precise transcriptional programs, led by transcription factors in combination with epigenetic events. Recent advances in epigenomic and transcriptomic techniques provided insight into different gene regulation mechanisms. However, to date it remains challenging to understand how combinations of transcription factors together with epigenetic events control cell-type specific gene expression. We have developed the AnnoMiner web-server, an innovative and flexible tool to annotate and integrate epigenetic, and transcription factor occupancy data. First, AnnoMiner annotates user-provided peaks with gene features. Second, AnnoMiner can integrate genome binding data from two different transcriptional regulators together with gene features. Third, AnnoMiner offers to explore the transcriptional deregulation of genes nearby, or within a specified genomic region surrounding a user-provided peak. AnnoMiner’s fourth function performs transcription factor or histone modification enrichment analysis for user-provided gene lists by utilizing hundreds of public, high-quality datasets from ENCODE for the model organisms human, mouse, Drosophila and C. elegans. Thus, AnnoMiner can predict transcriptional regulators for a studied process without the strict need for chromatin data from the same process. We compared AnnoMiner to existing tools and experimentally validated several transcriptional regulators predicted by AnnoMiner to indeed contribute to muscle morphogenesis in Drosophila. AnnoMiner is freely available at http://chimborazo.ibdm.univ-mrs.fr/AnnoMiner/.

4. Evolution of mechanisms controlling epithelial morphogenesis across animals: new insights from dissociation-reaggregation experiments in the sponge Oscarella lobularis Vernale, Amélie, Prünster, Maria Mandela, Marchiano, Fabio, Debost, Henry, Brouilly, Nicolas, Rocher, Caroline, Massey-Harroche, Dominique, Renard, Emmanuelle, Bivic, André Le, Habermann, Bianca H, and Borchiellini, Carole BMC 2021 [Abs] [DOI]

   To get insights into the early evolution of epithelial morphogenesis, we focused on morphogenic characteristics of the homoscleromorph sponge Oscarella lobularis. Homoscleromorpha are a sponge class with a typical basement membrane and adhaerens-like junctions unknown in other sponge classes. We took advantage of the dynamic context provided by cell dissociation-reaggregation experiments to explore morphogenetic processes in epithelial cells in a non-bilaterian lineage by combining fluorescent and electron microscopy observations and RNA sequencing approaches at key time-points of the dissociation and reaggregation processes.

2020

1. mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations Yim, Annie, Koti, Prasanna, Bonnard, Adrien, Marchiano, Fabio, Dürrbaum, Milena, Garcia-Perez, Cecilia, Villaveces, Jose, Gamal, Salma, Cardone, Giovanni, Perocchi, Fabiana, Storchova, Zuzana, and Habermann, Bianca H. Nucleic acids research 2020 [Abs] [DOI]

   Mitochondria participate in metabolism and signaling. They adapt to the requirements of various cell types. Publicly available expression data permit to study expression dynamics of genes with mitochondrial function (mito-genes) in various cell types, conditions and organisms. Yet, we lack an easy way of extracting these data for mito-genes. Here, we introduce the visual data mining platform mitoXplorer, which integrates expression and mutation data of mito-genes with a manually curated mitochondrial interactome containing ∼1200 genes grouped in 38 mitochondrial processes. User-friendly analysis and visualization tools allow to mine mitochondrial expression dynamics and mutations across various datasets from four model species including human. To test the predictive power of mitoXplorer, we quantify mito-gene expression dynamics in trisomy 21 cells, as mitochondrial defects are frequent in trisomy 21. We uncover remarkable differences in the regulation of the mitochondrial transcriptome and proteome in one of the trisomy 21 cell lines, caused by dysregulation of the mitochondrial ribosome and resulting in severe defects in oxidative phosphorylation. With the newly developed Fiji plugin mitoMorph, we identify mild changes in mitochondrial morphology in trisomy 21. Taken together, mitoXplorer (http://mitoxplorer.ibdm.univ-mrs.fr) is a user-friendly, web-based and freely accessible software, aiding experimental scientists to quantify mitochondrial expression dynamics.