Biology subjects

Gueguen, N.

Publications and source records attributed to Gueguen, N..

10 recordsLinked to original sources

bioRxiv2024

A human mitochondrial isoform of TRPV1 regulates intracellular Ca2+ simultaneously with mitochondrial thermolysis

Mitochondria are the cornerstones of cellular and body thermogenesis, with an inner temperature possibly reaching 50{degrees}C. Here, we report the identification of a human Transient Receptor Potential Vanilloid 1 alternative isoform located in mitochondria. This isoform, which we have termed mitoTRPV1, acts as a thermostat to restrict the mitochondrial temperature. The mitoTRPV1 open reading frame overlaps TRPV1 exons 1 and 2 and intron 2 in a +1 frame, encoding for a predicted 150 amino-acid N-terminal mitochondrial targeting sequence (MTS) conserved amongst mammalian species, followed by the 687 amino acids of TRPV1 C-terminal. This ORF is ubiquitously expressed in most human organs, underscoring its broad relevance. The deduced MTS, conserved among mammalian species, effectively addresses this TRPV1 isoform to the mitochondrial inner membrane. Our experiments, using heterologous wild-type and mutated mitoTRPV1 expression, combined with Ca2+ imaging, mitochondrial temperature and oxygraphy measurements, disclosed that mitoTRPV1 activation induces Ca2+ efflux and mitochondrial cooling, without modification of mitochondrial respiration and ATP production. Notably, the loss of function mitoTRPV1-G684V isoform, responsible for exertional heat stroke predisposition in humans, abolished mitochondrial Ca2+ efflux and cooling. These findings reveal a new thermolysis function for TRPV1 in preventing mitochondrial overwarming while not affecting the OXPHOS efficiency. They also highlight the potential implications of mitoTRPV1 in human diseases related to temperature dysregulation.

cell biology↗

bioRxiv2024

The transcription factor Traffic jam orchestrates the somatic piRNA pathway in Drosophila ovaries

The PIWI-interacting RNA (piRNA) pathway is essential for transposable element (TE) silencing in animal gonads. While the transcriptional regulation of piRNA pathway components in germ cells has been documented in mice and flies, their control in somatic cells of Drosophila ovaries remains unresolved. Here, we demonstrate that Traffic jam (Tj), the Drosophila orthologue of large Maf transcription factors in mammals, is a master regulator of the somatic piRNA pathway. Tj binds to regulatory regions of somatic piRNA factors and the major piRNA cluster flamenco, which carries a Tj-bound enhancer downstream of its promoter. Depletion of Tj in somatic follicle cells causes downregulation of piRNA factors, loss of flam expression and de-repression of gypsy-family TEs. We propose that the arms race between the host and TEs led to the co-evolution of promoters in piRNA pathway genes as well as TE regulatory regions that both rely on a shared transcription factor. Highlights- Traffic jam (Tj) acts as a master regulator of the somatic piRNA pathway in Drosophila. - Tj regulates a network of piRNA pathway genes, mirroring the gene-regulatory mechanism of A-MYB in the mouse testis and Ovo in fly ovaries. - Cis-regulatory elements with Tj motifs are present at the promoters of somatic piRNA pathway genes. - The expression of the flamenco piRNA cluster is directly controlled by Tj.

molecular biology↗

bioRxiv2024

Environmentally-informed functional characterization of a plastid diatom metabolic bridge of mitochondrial origin

Withdrawal statementThe authors have withdrawn this manuscript due to a duplicate posting of manuscript number BIORXIV/2022/507166. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. The correct preprint can be found at doi: 10.1101/2022.09.08.507166

evolutionary biology↗

bioRxiv2024

A dual histone code specifies the binding of heterochromatin protein Rhino to a subset of piRNA source loci

Animal germ cells deploy a specialized small RNA-based silencing system, called the PIWI-interacting RNA (piRNA) pathway, to prevent unwanted expression of transposable elements and maintain genome integrity. In Drosophila germ cells, the majority of piRNA populations originate from dual-strand piRNA clusters, genomic regions highly enriched in transposable element (TE) fragments, via an elaborate protein machinery centred on the heterochromatin protein 1 homolog, Rhino. Although Rhino binds to peptides carrying trimethylated H3K9 in vitro, it is not fully understood why in vivo only a fraction of H3K9me3-decorated heterochromatin is occupied by Rhino. Recent work revealed that Rhino is recruited to a subset of piRNA clusters by the zinc finger protein Kipferl. Here we identify a Kipferl-independent mode of Rhino targeting that, in addition to the previously established role of H3K9me3, also depends on the histone H3 lysine 27 methyltransferase Enhancer of Zeste. At Kipferl-independent sites, we find that Rhino, through its chromodomain, specifically binds to loci marked by both H3K9me3 and H3K27me3. Although the exact mechanism of how Rhino binding is influenced by dual histone modifications remains unclear from a structural and biochemical perspective, our work suggests that combinatorial modifications can play a crucial role in influencing the specificity of chromatin-binding protein interactions. These findings provide an enhanced understanding of the multifaceted mechanisms by which Rhino targets piRNA source loci highlighting the sophisticated epigenetic landscape governing TE silencing in Drosophila germ cells. Our work further reveals a role for dual histone modifications defining the binding specificity of a key chromatin protein.

molecular biology↗

bioRxiv2023

Encoding of the colorectal cancer metabolic program through MICU2

The mitochondrial Ca2+ uniporter (MCU) plays crucial role in intramitochondrial Ca2+ uptake, allowing Ca2+-dependent activation of oxidative metabolism. In recent decades, the role of MCU pore-forming proteins has been highlighted in cancer. However, the contribution of MCU-associated regulatory proteins mitochondrial calcium uptake 1 and 2 (MICU1 and MICU2) to pathophysiological conditions has been poorly investigated. Here, we describe the role of MICU2 in cell proliferation and migration using in vitro and in vivo models of colorectal cancer (CRC). Transcriptomic analysis demonstrated an increase in MICU2 expression and the MICU2/MICU1 ratio in advanced CRC and CRC-derived metastases. We report that expression of MICU2 is necessary for mitochondrial Ca2+ uptake and quality of the mitochondrial network. Our data reveal the interplay between MICU2 and MICU1 in the metabolic flexibility between anaerobic glycolysis and OXPHOS. Overall, our study sheds light on the potential role of the MICUs in diseases associated with metabolic reprogramming. HighlightsO_LIMICU2 plays a pivotal role in the balance between anaerobic glycolysis and oxidative phosphorylation C_LIO_LIMICU2 stabilizes the mitochondrial network and endoplasmic reticulum-mitochondrial calcium flux C_LIO_LIMICU2 expression and the MICU2/MICU1 ratio control proliferation and metastasis formation in colorectal cancer C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/564893v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@6bb307org.highwire.dtl.DTLVardef@b6a966org.highwire.dtl.DTLVardef@2ba053org.highwire.dtl.DTLVardef@2ab691_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

A comprehensive evolutionary scenario for the origin and neofunctionalization of the Drosophila speciation gene Odysseus (OdsH)

Odysseus (OdsH) was the first gene described in Drosophila related to speciation and hybrid sterility. This gene was first described in the melanogaster subgroup and more specifically in the sterile hybrids from crosses between D. mauritiana and D. simulans. Its origin is attributed to the duplication of the gene unc-4, which would have occurred in the ancestor of the subgenus Sophophora. By using a much larger sample of Drosophila species, we showed that contrary to what has been previously proposed, OdsH origin occurred approximately 62 million years ago (Mya). Then, OdsH have experienced rapid neofunctionalization in male reproductive tracts, evidenced by its evolutionary rates, expression and transcription factor binding sites. Furthermore, the analysis of the OdsH peptide sequence allowed the identification of mutations in the DNA- and protein-binding domains of D. mauritiana that could result in incompatibility with genomes from other species. We then explored the expression of OdsH in the spermatocytes of D. arizonae and D. mojavensis, a pair of recently diverged sister species with incomplete reproductive isolation and expected to find the involvement of OdsH in hybrid sterility. Our data indicated that OdsH expression is not atypical in male-sterile hybrids from these species. In conclusion, we have demonstrated that the origin of OdsH occurred earlier than previously proposed and that its neofunctionalization in male sexual functions occurred rapidly after its origin. Our results also suggested that its role as a speciation gene, as in the melanogaster subgroup of species, may be restricted to this specific taxon.

evolutionary biology↗

bioRxiv2023

Gap junction-dependent amino acid transfer promotes germ cell growth

Gap junctions allow the exchange of small molecules between cells. How this function could be used to promote cell growth is not yet fully understood. During Drosophila ovarian follicle development, germ cells, which are surrounded by epithelial somatic cells, undergo massive growth. We found that this growth depends on gap junctions between these cell populations, with a requirement for Innexin4 and Innexin2, in the germ cells and the somatic cells, respectively. Translatomic analyses revealed that somatic cells express enzymes and transporters involved in amino acid metabolism that are absent in germ cells. Among them, we identified an amino acid transporter required for germline growth. Its ectopic expression in the germline can compensate for its absence in somatic cells. Moreover, affecting either gap junctions or amino-acid import in somatic cells induces P-bodies in the germ cells, a feature associated with an arrest of translation. Finally, in somatic cells, innexin2 expression and gap junction assembly are regulated by the insulin receptor/PI3K kinase pathway. Overall, these results support the view that metabolic transfer through gap junction promotes cell growth and illustrate how such a mechanism can be integrated into a developmental programme, coupling growth control by extrinsic systemic signals with the intrinsic coordination between cell populations.

developmental biology↗

bioRxiv2022

A Plastidial Glycolytic-Gluconeogenic Switch of Mitochondrial Origin Enables Diatom Adaptations to High Latitudes

Organic carbon fixed in chloroplasts through the Calvin Cycle can be diverted towards different metabolic fates, including cytoplasmic and mitochondrial respiration; gluconeogenesis; and synthesis of diverse plastid metabolites via the pyruvate hub. In plants, pyruvate is principally produced via cytoplasmic glycolysis, although a plastid-targeted lower glycolytic pathway is known in non-photosynthetic tissue. Here, we characterize a lower plastid glycolytic-gluconeogenesis pathway in diatoms, ecologically important marine algae distantly related to plants. We show that two reversible enzymes required to complete diatom plastid glycolysis-gluconeogenesis, Enolase and PGAM (bis- phospho-glycerate mutase), originated through duplications of mitochondria-targeted respiratory isoforms. Through CRISPR-Cas9 mutagenesis, integrative omic analyses, and measured kinetics of expressed enzymes in the diatom Phaeodactylum tricornutum, we present evidence that this pathway diverts plastid glyceraldehyde-3-phosphate into the pyruvate hub, and may also function in the gluconeogenic direction. Considering experimental data, we show that this pathway has different roles dependent in particular on day length and environmental temperature, and show that it is expressed at elevated levels in high latitude oceans where diatoms are abundant. Our data provide evolutionary, meta-genomic and functional insights into a poorly understood yet evolutionarily recurrent plastid metabolic pathway.

plant biology↗

bioRxiv2022

Germline piRNAs counteract endogenous retrovirus invasion from somatic cells.

Most Drosophila transposable elements (TEs) are LTR retrotransposons, some of which belong to the genus Errantivirus and share structural and functional characteristics with vertebrate endogenous retroviruses (ERVs). These virus-derived elements occupy a large part of the genome, but it is unclear whether and how they can be reactivated and if they retain their replication capacity. We created conditions where control of the Drosophila ZAM errantivirus through the piRNA pathway was abolished leading to its reactivation in real time in somatic gonadal cells. We show that ZAM may remain active in these cells indicating that errantiviruses may hide from the efficient germline piRNA pathway by being expressed exclusively in somatic cells. After reactivation, ZAM invaded the oocytes and severe fertility defects were observed. The germline then set up its own adaptive genomic immune response against the constantly invading errantivirus, restricting invasion and restoring fertility. Our results not only highlight how errantiviruses and their host adapt to each other but also reveal a time window during oogenesis that may be favourable for viral germline invasion and endogenization.

genetics↗

bioRxiv2018

Environmentally-induced epigenetic conversion of a piRNA cluster

Transposable element (TE) activity is repressed in animal gonads by PIWI-interacting RNAs (piRNAs), a class of small RNAs produced by specific loci made of TEs insertions and fragments. Current models propose that these loci are functionally defined by the maternal inheritance of piRNAs produced during the previous generation, raising the question of their first activation in the absence of piRNAs. Taking advantage of an inactive cluster of P-element derived transgene insertions, we show here that raising flies at high temperature (29{degrees}C) instead of 25{degrees}C results in a rare but invasive epigenetic conversion of this locus into an active piRNAs producing one. The newly acquired epigenetic state is stable over many generations even when flies are switch back to 25{degrees}C. The silencing capacities, piRNA production and chromatin modifications of the cluster are all identical whether conversion occurred by maternal piRNA inheritance or by high temperature. We also demonstrate that in addition to high temperature, a single homologous transgene inserted elsewhere in the genome is required to activate the locus. We thus have identified a minimal system of three components to create a stable piRNA producing locus: 1) a locus with multiple TE derived sequences; 2) an euchromatic copy of these sequences and 3) elevated temperature. Altogether, these data report the first case of the establishment of an active piRNA cluster by environmental changes. It highlights how such variations of species natural habitat can become heritable and shape their epigenome.\n\nSIGNIFICANCE STATEMENTRecently, we have witnessed great progress in our understanding of the silencing of Transposable Elements (TEs) by piRNAs, a class of small RNAs produced by piRNA clusters. At each generation, piRNA clusters are supposed to be activated by homologous piRNAs inherited from the mother raising the question of the making of the first piRNAs. Here, we report the birth of a stable and functional piRNA cluster induced by high temperature without maternal inheritance of homologous piRNAs. We propose a minimal system to create a piRNA cluster: a sufficient number of repeated sequences, a euchromatic copy of these sequences and an increase in the production of antisense RNA.

genetics↗