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- Sex-specific transcriptome similarity networks elucidate comorbidity relationshipsPublication . Sánchez-Valle, Jon; Flores-Rodero, María; Costa, Felipe Xavier; Carbonell-Caballero, Jose; Núñez-Carpintero, Iker; Tabarés-Seisdedos, Rafael; Rocha, Luis Mateus; Cirillo, Davide; Valencia, AlfonsoHumans present sex-driven biological differences. Consequently, the prevalence of analyzing specific diseases and comorbidities differs between the sexes, directly impacting patients’ management and treatment. Despite its relevance and the growing evidence of said differences across numerous diseases (with 4,370 PubMed results published within the past year), knowledge at the comorbidity level remains limited. In fact, to date, no study has attempted to identify the biological processes altered differently in women and men, promoting differences in comorbidities. To shed light on this problem, we analyze expression data for more than 100 diseases from public repositories, analyzing each sex independently. We calculate similarities between differential expression profiles by disease pairs and find that 13-16% of transcriptomically similar disease pairs are sex-specific. By comparing these results with epidemiological evidence, we recapitulate 53-60% of known comorbidities distinctly described for men and women, finding sex-specific transcriptomic similarities between sex-specific comorbid diseases. The analysis of shared underlying pathways shows that diseases can co-occur in men and women by altering alternative biological processes. Finally, we identify different drugs differentially associated with comorbid diseases depending on patients’ sex, highlighting the need to consider this relevant variable in the administration of drugs due to their possible influence on comorbidities.
- Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillasPublication . Bowman, Jacob D.; Silva, Neide; Schüftan, Erik; Almeida, Joana M.; Brattig-Correia, Rion; Oliveira, Raquel A.; Tüttelmann, Frank; Enard, David; Navarro-Costa, Paulo; Lynch, Vincent J.Gorillas have a polygynous social system in which the highest-ranking male has almost exclusive access to females and sires most of the offspring in the troop. Such behavior results in a dramatic reduction of sperm competition, which is ultimately associated with numerous traits that cause low efficacy of gorilla spermatogenesis. However, the molecular basis behind the remarkable erosion of the gorilla male reproductive system remains unknown. Here, we explored the genetic consequences of the polygynous social system in gorillas by testing for altered selection intensity across 13,310 orthologous protein-coding genes from 261 Eutherian mammals. We identified 578 genes with relaxed purifying selection in the gorilla lineage, compared with only 96 that were positively selected. Genes under relaxed purifying selection in gorillas have accumulated numerous deleterious amino acid substitutions, their expression is biased towards male germ cells, and are enriched in functions related to meiosis and sperm biology. We tested the function of gorilla relaxed genes previously not implicated in sperm biology using the Drosophila model system and identified 41 novel spermatogenesis genes required for normal fertility. Furthermore, by exploring exome/genome sequencing data of infertile men with severe spermatogenic impairment, we found that the human orthologs of the gorilla relaxed genes are enriched for loss-of-function variants in infertile men. These data provide compelling evidence that reduced sperm competition in gorillas is associated with relaxed purifying selection on genes related to male reproductive function. The accumulation of deleterious mutations in these genes likely provides the mechanistic basis behind the low efficacy of gorilla spermatogenesis and uncovers new candidate genes for human male infertility.
- Evolutionary immunology to explore original antiviral strategiesPublication . Imler, Jean-Luc; Cai, Hua; Meignin, Carine; Martins, NelsonOver the past 25 years, the field of evolutionary developmental biology (evo-devo) has used genomics and genetics to gain insight on the developmental mechanisms underlying the evolution of morphological diversity of animals. Evo-devo exploits the key insight that conserved toolkits of development (e.g., Hox genes) are used in animals to produce genetic novelties that provide adaptation to a new environment. Like development, immunity is forged by interactions with the environment, namely the microbial world. Yet, when it comes to the study of immune defence mechanisms in invertebrates, interest primarily focuses on evolutionarily conserved molecules also present in humans. Here, focusing on antiviral immunity, we argue that immune genes not conserved in humans represent an unexplored resource for the discovery of new antiviral strategies. We review recent findings on the cGAS-STING pathway and explain how cyclic dinucleotides produced by cGAS-like receptors may be used to investigate the portfolio of antiviral genes in a broad range of species. This will set the stage for evo-immuno approaches, exploiting the investment in antiviral defences made by metazoans over hundreds million years of evolution.
- A non-genetic model of vascular shunts informs on the cellular mechanisms of formation and resolution of arteriovenous malformationsPublication . Ouarné, Marie; Pena, Andreia; Ramalho, Daniela; Conchinha, Nadine V.; Costa, Tiago; Figueiredo, Ana; Saraiva, Marta Pimentel; Carvalho, Yulia; Misikova, Lenka Henao; Oh, S. Paul; Franco, Cláudio A.Arteriovenous malformations (AVMs), a disorder characterized by direct shunts between arteries and veins, are associated with genetic mutations. However, the mechanisms leading to the transformation of a capillary into a shunt remain unclear and how shunts can be reverted into capillaries is poorly understood. Here, we report that oxygen-induced retinopathy (OIR) protocol leads to the consistent and stereotypical formation of AV shunts in non-genetically altered mice. OIR-induced AV shunts show all the canonical markers of AVMs. Genetic and pharmacological interventions demonstrated that changes in endothelial cell (EC) volume of venous origin (hypertrophic venous cells) are the initiating step promoting AV shunt formation, whilst EC proliferation or migration played minor roles. Inhibition of mTOR pathway prevents pathological increases in EC volume and significantly reduces the formation of AV shunts. Importantly, we demonstrate that ALK1 signaling cell-autonomously regulates EC volume, demonstrating that our discoveries link with hereditary hemorrhagic telangiectasia (HHT)-related AVMs. Finally, we demonstrate that a combination of EC volume control and EC migration is associated with the regression of AV shunts. We demonstrate that an increase in the EC volume is the key mechanism driving the initial stages of AV shunt formation, leading to asymmetric capillary diameters. Based on our results, we propose a coherent and unifying timeline leading to the fast conversion of a capillary vessel into an AV shunt. Our data advocates for further investigation into the mechanisms regulating EC volume in health and disease as a way to identify therapeutic approaches to prevent and revert AVMs.
- Investigation of Trypanosoma-induced vascular damage sheds insights into Trypanosoma vivax sequestrationPublication . Pereira, Sara Silva; Brás, Daniela; Porqueddu, Teresa; Nascimento, Ana M.; Niz, Mariana DeMultiple blood-borne pathogens infecting mammals establish close interactions with the host vascular endothelium as part of their life cycles. In this work, we investigate differences in the interactions of three Trypanosoma species: T. brucei, T. congolense and T. vivax with the blood vasculature. Infection with these species results in vastly different pathologies, including different effects on vascular homeostasis, such as changes in vascular permeability and microhemorrhages. While all three species are extracellular parasites, T. congolense is strictly intravascular, while T. brucei is capable of surviving both extra- and intravascularly. Our knowledge regarding T. vivax tropism and its capacity of migration across the vascular endothelium is unknown. In this work, we show for the first time that T. vivax parasites sequester to the vascular endothelium of most organs, and that, like T. congolense, T. vivax Y486 is largely incapable of extravasation. Infection with this parasite species results in a unique effect on vascular endothelium receptors including general downregulation of ICAM1 and ESAM, and upregulation of VCAM1, CD36 and E-selectin. Our findings on the differences between the two sequestering species (T. congolense and T. vivax) and the non-sequestering, but extravasating, T. brucei raise important questions on the relevance of sequestration to the parasite’s survival in the mammalian host, and the evolutionary relevance of both sequestration and extravasation.
- Novel pathways converge with quorum sensing to regulate plant and insect host-specific factors in Erwinia carotovoraPublication . Vieira, Filipe J. D.; Teixeira, Luís; Xavier, Karina B.Erwinia carotovora Ecc15 is a vector-borne phytopathogen that relies on insects to be transmitted between plant hosts. To interact with its hosts, this bacterium depends on host-specific bacterial traits. Plant tissue maceration depends on production of plant cell wall degrading enzymes (PCWDE), while survival in the digestive tract of the insect requires the Erwinia virulence factor (evf). Evf expression is responsible for the cost of Ecc15 infection in Drosophila melanogaster and overexpression is lethal to the insect host. Therefore, its expression must be well controlled. Expression of evf and PCWDEs is co-regulated by quorum sensing via the transcriptional regulator Hor. Since virulence factors are often controlled by multiple signals, we asked which additional factors regulate evf expression. Using a genetic screen, we identified the sensor histidine kinase arcB and a new TetR-like regulator (named herein as lvtR, after Low Virulence Transcriptional Repressor), as novel regulators not only of evf, but also of pelA, which encodes a major PCWDE. We further demonstrate that arcB and lvtR mutants have reduced plant tissue maceration and reduced development delay and lethality in Drosophila melanogaster, compared to wild-type bacteria. Thus showing the importance of these regulators in the establishment of Erwinia-host-vector interactions. We also found that ArcB and LvtR regulation converges on Hor, independently of quorum sensing, to co-regulate expression of both plant and insect bacterial interaction factors during plant infection. Taken together, our results reveal a novel regulatory hub that enables Ecc15 to integrate quorum sensing responses and environmental cues to co-regulate traits required for infection of both the plant and the insect vector. Moreover, we show that ArcB regulation of bacteria-host interaction processes is conserved in other bacteria.
- ATG9A facilitates the biogenesis of influenza A virus liquid condensates near the ER by dissociating recycling vesicles from microtubulesPublication . Vale-Costa, Sílvia; Etibor, Temitope Akghibe; Brás, Daniela; Sousa, Ana Laura; Amorim, Maria JoãoMany viruses that threaten public health establish condensates via phase transitions to complete their lifecycles, and knowledge on such processes is key for the design of new antivirals. In the case of influenza A virus, liquid condensates known as viral inclusions are sites dedicated to the assembly of its 8-partite RNA genome. Liquid viral inclusions emerge near the endoplasmic reticulum (ER) exit sites, but we lack the molecular understanding on how the ER contributes to their biogenesis. We show here that viral inclusions develop at remodeled ER sites and display dynamic interactions using the ER, including fusion and fission events and sliding movements. We also uncover a novel role for the host factor, ATG9A, in mediating the exchange of viral inclusions between the ER and microtubules. Depletion of ATG9A arrests viral inclusions at microtubules and prevents their accumulation at the ER, leading to a significantly reduced production of viral genome complexes and infectious virions. In light of our recent findings, we propose that a remodeled ER supports the dynamics of liquid IAV inclusions, with ATG9A acting locally to facilitate their formation. This work advances our current knowledge regarding influenza genome assembly, but also reveals new roles for ATG9A beyond its classical involvement in autophagy.
- An SNF2 helicase-like protein links mitotic transcription termination to sister chromatid resolutionPublication . Carmo, Catarina; Coelho, João; Silva, Rui; Tavares, Alexandra; Boavida, Ana; Gaetani, Paola; Martinho, Rui Gonçalo; Oliveira, Raquel A.Mitotic chromatin is largely assumed incompatible with transcription due to changes in the transcription machinery and chromosome architecture. However, the mechanisms of mitotic transcriptional inactivation and their interplay with chromosome assembly remain largely unknown. By monitoring ongoing transcription in Drosophila early embryos, we reveal that eviction of nascent mRNAs from mitotic chromatin occurs after substantial chromosome compaction and is not promoted by condensin I. Instead, we show that the timely removal of transcripts from mitotic chromatin is driven by the SNF2 helicase-like protein Lodestar (Lds), identified here as a modulator of sister chromatid cohesion defects. In addition to transcriptional termination, we uncovered that Lds cooperates with Topoisomerase 2 to ensure efficient sister chromatid resolution and mitotic fidelity. We conclude that mitotic transcriptional termination is not a passive consequence of cell cycle progression and/or chromosome compaction but occurs via dedicated mechanisms with functional parallelisms to sister chromatid resolution.