2026
Summary
- Team of J. Soutourina received the label from Ligue Nationale contre le cancer
- Actomyosin-dependent assembly of the mechanosensitive machinery from adherens junctions triggers actin polymerization and organization
- The heme A synthase Cox15, as a target of redox-active 3-benzylmenadiones with antiparasitic activity
- How virulence genes reorganize the Salmonella genome
- Gain and loss of gene function shaped the nickel hyperaccumulation trait in Noccaea caerulescens
- Cross-regulation of iron-sulfur cluster biosynthesis by frataxin and ferredoxin-2
Understand how the essential complexes, the coregulator Mediator and the chromatin remodeling complex RSC/PBAF, cooperate in the nucleus.
In eukaryotes, transcription and DNA repair occur in the crowded context of chromatin. Dysfunctions of these processes can lead to cancers. Mediator is an essential and conserved multisubunit coactivator complex, mutated in many cancers. However, it remains largely unknown how Mediator and chromatin regulators coordinate their functions. Our recent publication suggests the novel hypothesis that Mediator acts in conjunction with the chromatin remodeling complex RSC (Remodels the Structure of Chromatin) of SWI/SNF family, homologous to PBAF (Polybromo-associated BAF) in human, representing the most frequently mutated complexes in cancers. In this project supported by Ligue Nationale contre le cancer, using the yeast model with a perspective to extend the study to human cells, we intend to decipher the molecular mechanisms involved in functional cooperation between these essential coregulator complexes in transcription regulation, DNA repair and chromatin organization relevant for cancer biology.
Contact: Julie SOUTOURINA <julie.soutourina@i2bc.paris-saclay.fr>
In ScienceAdvances
Adherens junction mechanosensing.
To form tissues, cells adhere to one another through structures known as adherens junctions. These junctions have the ability to adapt to the mechanical variations to which tissues are subjected, thereby preserving their integrity.
In this study published in Science Advances, we studied this mechanism by combining various biochemical approaches, including an unprecedented in vitro reconstitution involving surface micropatterning and up to eight purified proteins.
We show that contraction of the actomyosin cytoskeleton is sufficient to trigger the assembly of three key proteins—α-catenin, vinculin, and VASP. Once associated, these proteins cooperate to polymerize and reorganize actin.
These findings reveal how adherens junctions sense and adapt to mechanical forces exerted by the cytoskeleton by strengthening their connection to it, thereby contributing to tissue cohesion and stability..
More information: https://www.science.org/doi/10.1126/sciadv.ady4863
Contact: Christophe LE CLAINCHE <christophe.leclainche@i2bc.paris-saclay.fr>
In Antimicrobial Agents and Chemotherapy
We identified a new target for antiparasitic compounds and it is in the mitochondria.
Chagas disease, caused by Trypanosoma cruzi, is a neglected parasitic infection. The very limited arsenal of anti-T. cruzi treatments calls for the development of new drugs. Recently, a library of 3-benzylmenadione derivatives was synthesized with cruzidione being the most efficient and specific compound against the parasite. To decipher its mode of action, we used the yeast Saccharomyces cerevisiae as model. Evidence pinpointed at the heme A synthase Cox15 as a primary target of cruzidione: 1) a mutation in Cox15 (i.e., S429F) renders the yeast cells highly sensitive to the drug, 2) treatment with cruzidione led to the loss of cytochrome c oxidase, an enzyme that relies on heme A as an essential cofactor and 3) replacement of the yeast Cox15 by T. cruzi enzyme resulted in a high sensitivity to cruzidione. We then investigated the effect of cruzidione in T. cruzi and observed a significant reduction of heme contents, most likely involving the inhibition of the heme A synthase. This, in turn, led to a decrease in O2 consumption by the parasite. Finally, using the yeast model, we showed that, similarly to what we previously found for the antimalarial benzylmenadione plasmodione, NADH-dehydrogenase plays a key role in cruzidione bioactivation. We proposed that the reduced benzoylmenadione metabolites produced by the reaction with NADH-dehydrogenase, act as Cox15 inhibitors. This study, through the identification of the mode of action of cruzidione, highlighted Cox15 as a novel target for antiparasitic drugs.
More information: https://journals.asm.org/doi/10.1128/aac.01161-25
Contact: Brigitte MEUNIER <brigitte.meunier@i2bc.paris-saclay.fr>
How virulence genes reorganize the Salmonella genome
In Nature Communications
Using functional genomics in sorted Salmonella populations and high-resolution microscopy, the authors show that the expression of Pathogenicity Island 1 is associated with chromatin remodeling and with the repositioning of this region toward the nucleoid periphery.
Chromatin provides a universal framework for organizing and regulating genomes across the three domains of life. In bacteria, it is composed of intrinsically supercoiled DNA associated with small DNA-binding proteins known as nucleoid-associated proteins (NAPs). Their binding can induce DNA bending, bridging, coating, and/or wrapping, giving rise to distinct modes of chromatin organization.
Bacterial chromatin can exist in a repressed state (silent chromatin) or in an actively transcribed state (active chromatin). Silent chromatin is largely associated with H-NS, a xenogeneic silencer that restricts the costly expression of genes acquired by horizontal transfer. In contrast, active chromatin is densely occupied by RNA polymerase and is characterized by different levels of DNA supercoiling. However, the changes in protein occupancy and chromatin organization that accompany transitions between these two states remain poorly understood.
Researchers of the Genome Biology Department of the I2BC in collaboration with the NGS and the Imaging facility of the I2BC and the Trinity College Dublin (Ireland), have unveiled the chromatin organization of horizontally acquired regions in Salmonella enterica serovar Typhimurium, which are essential for its pathogenicity. They show that expression of Pathogenicity Island 1 (SPI-1) is accompanied by local chromatin remodeling, marked by profound changes in three-dimensional organization and protein occupancy. This remodeling is also associated with the repositioning of SPI-1 toward the nucleoid periphery.
These findings provide new insights into the interplay between xenogeneic silencing, counter-silencing mechanisms, chromatin architecture, and the evolutionary integration of acquired DNA. They also reveal a finely tuned chromatin remodeling process that minimizes the cellular cost of activating pathogenicity islands, and they establish a direct link between the linear (1D) organization of the genome and its three-dimensional (3D) folding.
More information: https://www.nature.com/articles/s41467-025-67746-w
Contact: Virginia LIOY <virginia.lioy@i2bc.paris-saclay.fr>
Gain and loss of gene function shaped the nickel hyperaccumulation trait in Noccaea caerulescens
In The Plant Cell
Plants that hyperaccumulate nickel open the possibility to mine this metal from soils in an environmetally friendly manner. In this study, sequencing of a nickel hyperaccumulating plant together with genomic and transcriptomic comparisons reveal the molecular mechanisms underlying this extreme trait.
Nickel hyperaccumulation is an extreme adaptation to ultramafic soils observed in more than 500 plant species. However, our understanding of the molecular mechanisms underlying the evolution of this trait remains limited. To shed light on these mechanisms, we have generated a high-quality genome assembly of the metal hyperaccumulator Noccaea caerulescens. We then used this genome as reference to conduct comparative intraspecific and interspecific transcriptomic analyses using various accessions of N. caerulescens and the non-accumulating relative Microthlaspi perfoliatum to identify genes associated with nickel hyperaccumulation.
Our results suggest a correlation between nickel hyperaccumulation and a decrease in the expression of genes involved in defense responses and the regulation of membrane trafficking. Surprisingly, these analyses did not reveal a significant enrichment of genes involved in the regulation of metal homeostasis. However, we found that the expression levels of selected metal transporter genes, namely, NcHMA3, NcHMA4, and NcIREG2, are consistently elevated in N. caerulescens accessions hyperaccumulating nickel.
Furthermore, our analyses identified frameshift mutations in NcIRT1 associated with the loss of nickel hyperaccumulation in a few accessions. We further showed that the expression of a functional NcIRT1 in the roots of the La Calamine accession increases nickel accumulation in shoots. Our results demonstrate that NcIRT1 participates in nickel hyperaccumulation in N. caerulescens. They also suggest that nickel hyperaccumulation is an ancient trait in N. caerulescens that has evolved from the high and constitutive expression of several metal transporters, including NcIREG2, and that the trait was subsequently lost in a few accessions due to mutations in NcIRT1.
More information: https://doi.org/10.1093/plcell/koaf281
Contact: Sébastien THOMINE <sebastien.thomine@i2bc.paris-saclay.fr>
Cross-regulation of iron-sulfur cluster biosynthesis by frataxin and ferredoxin-2
In Nature
Tight regulation of Fe-S clusters biosynthesis via a mutually antagonistic binding of frataxin and ferredoxin-2 to the assembly machinery, with several important implications for the Friedreich’s ataxia disease caused by frataxin deficiency.
Iron-sulfur (Fe-S) clusters are essential metallocofactors that perform a multitude of biological functions. They are synthesized de novo by multi-proteins machienries and any defect in their synthesis leads to severe diseases such as Friedreich’s ataxia (FRDA), caused by defective expression of frataxin (FXN). Here, we uncover that efficient [2Fe-2S] cluster assembly requires a fine-tuned balanced ratio of FXN and Ferredoxin-2 (FDX2), an essential enzyme of the assembly process. [2Fe-2S] clusters are assembled on the scaffold protein ISCU2 with sulfur provided as a persulfide by NFS1, which is cleaved into sulfide by FDX2. FXN stimulates the whole process by accelerating persulfide transfer to ISCU2. Using an in vitro reconstituted human system, we show that any deviation from a close-to-equal amount of FXN or FDX2 downregulates Fe-S cluster synthesis. We performed a structure-function investigation, which revealed that this is due to competition between FXN and FDX2 for the same binding site on the NFS1-ISCU2 complex. We found that higher levels of FXN impair the persulfide-reductase activity of FDX2 and higher levels of FDX2 slow FXN-accelerated persulfide transfer to ISCU2. We also discovered that FDX2 directly hinders persulfide generation and transfer to ISCU2 by interacting with the persulfide-carrying mobile loop of NFS1. We further found that knocking-down FDX2 expression in a FRDA drosophila model, increases fly lifespan. Altogether, this work highlights a direct regulation of Fe-S cluster biosynthesis through antagonistic binding of FXN and FDX2 and suggests that decreasing FDX2 in the context of FXN deficiency in FRDA might constitute a novel therapeutic axis.
More information: https://www.nature.com/articles/s41586-025-09822-1
Contact: Benoit D’AUTRÉAUX <benoit.dautreaux@i2bc.paris-saclay.fr>