ORCID Profile
0000-0001-5245-2365
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Publisher: Cold Spring Harbor Laboratory
Date: 09-08-2022
DOI: 10.1101/2022.08.08.503231
Abstract: COVID-19 induces chromatin remodeling in host immune cells, and it had previously been shown that vitamin B12 downregulates some inflammatory genes via methyl-dependent epigenetic mechanisms. In this work, whole blood cultures from moderate or severe COVID-19 patients were used to assess the potential of B12 as adjuvant drug. The vitamin normalized the expression of a panel of inflammatory genes still dysregulated in the leukocytes despite glucocorticoid therapy during hospitalization. B12 also increased the flux of the sulfur amino acid pathway, raising the bioavailability of methyl. Accordingly, B12-induced downregulation of CCL3 strongly and negatively correlated with the hypermethylation of CpGs in its regulatory regions. Transcriptome analysis revealed that B12 attenuates the effects of COVID-19 on most inflammation-related pathways affected by the disease. As far as we are aware, this is the first study to demonstrate that pharmacological modulation of epigenetic marks in leukocytes favorably regulates central components of COVID-19 physiopathology. B12 has great potential as an adjuvant drug for alleviating inflammation in COVID-19.
Publisher: Cold Spring Harbor Laboratory
Date: 04-06-2019
DOI: 10.1101/659490
Abstract: Long non-coding RNAs (lncRNAs) have emerged as key coordinators of biological and cellular processes. Characterizing lncRNA expression across cells and tissues is key to understanding their role in determining phenotypes including human diseases. We present here FC-R2 , a comprehensive expression atlas across a broadly-defined human transcriptome, inclusive of over 109,000 coding and non-coding genes, as described in the FANTOM CAGE-Associated Transcriptome (FANTOM-CAT) study. This atlas greatly extends the gene annotation used in the original recount2 resource. We demonstrate the utility of the FC-R2 atlas by reproducing key findings from published large studies and by generating new results across normal and diseased human s les. In particular, we (a) identify tissue specific transcription profiles for distinct classes of coding and non-coding genes, (b) perform differential expression analyses across thirteen cancer types, providing new insights linking promoter and enhancer lncRNAs expression to tumor pathogenesis, and (c) confirm the prognostic value of several enhancers in cancer. Comprised of over 70,000 s les, the FC-R2 atlas will empower other researchers to investigate functions and biological roles of both known coding genes and novel lncRNAs. Most importantly, access to the FC-R2 atlas is available from jhubiostatistics.shinyapps.io/recount/ , the recount Bioconductor package, and cr2.html .
Publisher: Cold Spring Harbor Laboratory
Date: 09-10-2020
DOI: 10.1101/2020.10.08.332049
Abstract: PTEN is the most frequently lost tumor suppressor in primary prostate cancer (PCa) and its loss is associated with aggressive disease. However, the transcriptional changes associated with PTEN loss in PCa have not been described in detail. Here, we applied a meta-analysis approach, leveraging two large PCa cohorts with experimentally validated PTEN and ERG status, to derive a transcriptomic signature of PTEN loss, while also accounting for potential confounders due to ERG rearrangements. Strikingly, the signature indicates a strong activation of both innate and adaptive immune systems upon PTEN loss, as well as an expected activation of cell-cycle genes. Moreover, we made use of our recently developed FC-R2 expression atlas to expand this signature to include many non-coding RNAs recently annotated by the FANTOM consortium. With this resource, we analyzed the TCGA-PRAD cohort, creating a comprehensive transcriptomic landscape of PTEN loss in PCa that comprises both the coding and an extensive non-coding counterpart.
Publisher: Cold Spring Harbor Laboratory
Date: 20-02-2020
Abstract: Long noncoding RNAs (lncRNAs) have emerged as key coordinators of biological and cellular processes. Characterizing lncRNA expression across cells and tissues is key to understanding their role in determining phenotypes, including human diseases. We present here FC-R2, a comprehensive expression atlas across a broadly defined human transcriptome, inclusive of over 109,000 coding and noncoding genes, as described in the FANTOM CAGE-Associated Transcriptome (FANTOM-CAT) study. This atlas greatly extends the gene annotation used in the original recount2 resource. We demonstrate the utility of the FC-R2 atlas by reproducing key findings from published large studies and by generating new results across normal and diseased human s les. In particular, we (a) identify tissue-specific transcription profiles for distinct classes of coding and noncoding genes, (b) perform differential expression analysis across thirteen cancer types, identifying novel noncoding genes potentially involved in tumor pathogenesis and progression, and (c) confirm the prognostic value for several enhancer lncRNAs expression in cancer. Our resource is instrumental for the systematic molecular characterization of lncRNA by the FANTOM6 Consortium. In conclusion, comprised of over 70,000 s les, the FC-R2 atlas will empower other researchers to investigate functions and biological roles of both known coding genes and novel lncRNAs.
Publisher: Cold Spring Harbor Laboratory
Date: 13-04-2023
DOI: 10.1101/2023.04.12.536671
Abstract: Splicing is a highly conserved, intricate mechanism intimately linked to transcription elongation, serving as a pivotal regulator of gene expression. Alternative splicing may generate specific transcripts incapable of undergoing translation into proteins, designated as unproductive. A plethora of respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), strategically manipulate the host’s splicing machinery to circumvent antiviral responses. During the infection, SARS-CoV-2 effectively suppresses interferon (IFN) expression, leading to B cell and CD8+ T cell leukopenia, while simultaneously increasing the presence of macrophages and neutrophils in patients with severe COVID-19. In this study, we integrated publicly available omics datasets to systematically analyze transcripts at the isoform level and delineate the nascent-peptide translatome landscapes of SARS-CoV-2-infected human cells. Our findings reveal a hitherto uncharacterized mechanism whereby SARS-CoV-2 infection induces the predominant expression of unproductive splicing isoforms in key IFN signaling genes, interferon-stimulated genes (ISGs), class I MHC genes, and splicing machinery genes, including IRF7, OAS3, HLA-B, and HNRNPH1. In stark contrast, cytokine and chemokine genes, such as IL6, CXCL8, and TNF, predominantly express productive (protein-coding) splicing isoforms in response to SARS-CoV-2 infection. We postulate that SARS-CoV-2 employs a previously unreported tactic of exploiting the host splicing machinery to bolster viral replication and subvert the immune response by selectively upregulating unproductive splicing isoforms from antigen presentation and antiviral response genes. Our study sheds new light on the molecular interplay between SARS-CoV-2 and the host immune system, offering a foundation for the development of novel therapeutic strategies to combat COVID-19.
Publisher: Cold Spring Harbor Laboratory
Date: 11-03-2019
DOI: 10.1101/574343
Abstract: The protozoan Trypanosoma cruzi ( T. cruzi ) is a well-adapted parasite to mammalian hosts and the pathogen of Chagas disease in humans. As both host and T. cruzi are highly genetically erse, many variables come into play during infection, making disease outcomes difficult to predict. One important challenge in the field of Chagas disease research is determining the main factors leading to parasite establishment in the chronic stage in some organs, mainly the heart and/or digestive system. Our group previously showed that distinct strains of T. cruzi (JG and Col1.7G2) acquired differential tissue distribution in the chronic stage in dually-infected BALB/c mice. To investigate changes in the host triggered by the two distinct T. cruzi strains, we assessed the gene expression profile of BALB/c mouse hearts infected with either JG, Col1.7G2 or an equivalent mixture of both parasites during the initial phase of infection. This study demonstrates a clear distinction in host gene expression modulation by both parasites. Col1.7G2 strongly activated Th1-polarized immune signature genes, whereas JG showed only minor activation of the host immune response. Moreover, JG strongly reduced the expression of genes for ribosomal proteins and mitochondrial proteins related to the electron transport chain. Interestingly, evaluation of gene expression in mice inoculated with the mixture of parasites showed expression profiles for both up- and down-regulated genes, indicating the coexistence of both parasite strains in the heart during the acute phase. This study suggests that different strains of T. cruzi may be distinguished by their efficiency in activating the immune system, modulating host energy and reactive oxygen species production and decreasing protein synthesis during early infection, which may be crucial in defining parasite persistence in specific organs. The causative agent of Chagas disease, Trypanosoma cruzi , retains high genetic ersity, and its populations vary greatly across geographic locations. The T. cruzi mammalian hosts, including humans, also have high genetic variation, making it difficult to predict the disease outcome. Accordingly, this variability must be taken into account in several studies aiming to interrogate the effect of polyparasitism in drug trials, vaccines, diagnosis or basic research. Therefore, there is a growing need to consider the interaction between the pathogen and the host immune system in mixed infections. In the present work, we present an in-depth analysis of the gene expression of hearts from BALB/c mice infected with Col1.7G2 and JG alone or a mixture of both strains. Col1.7G2 induced a higher Th1 inflammatory response, while JG exhibited a weaker activation of immune response genes. Furthermore, JG-infected mice showed a notable reduction in the expression of genes responsible for mitochondrial oxidative phosphorylation and protein synthesis. Interestingly, the mixture-infected group displayed changes in gene expression as caused by both strains. Overall, we provided new insights into the host-pathogen interaction in the context of single and dual infection, showing remarkable differences in host gene expression modulation by two T. cruzi strains.
Publisher: Cold Spring Harbor Laboratory
Date: 16-08-2021
DOI: 10.1101/2021.08.16.456539
Abstract: The growth of sequenced bacterial genomes has revolutionized the assessment of microbial ersity. Pseudomonas is a widely erse genus, containing more than 254 species. Although type strains have been employed to estimate Pseudomonas ersity, they represent a small fraction of the genomic ersity at a genus level. We used 10,035 available Pseudomonas genomes, including 210 type strains, to build a genomic distance network to estimate the number of species through community identification. We identified taxonomic inconsistencies with several type strains and found that 25.65% of the Pseudomonas genomes deposited on Genbank are misclassified. The phylogenetic tree using single-copy genes from representative genomes in each species cluster in the distance network revealed at least 14 Pseudomonas groups, including P. alcaligenes group proposed here. We show that Pseudomonas is likely an admixture of different genera and should be further ided. This study provides an overview of Pseudomonas ersity from a network and phylogenomic perspective that may help reduce the propagation of mislabeled Pseudomonas genomes.
Publisher: Cold Spring Harbor Laboratory
Date: 22-12-2020
DOI: 10.1101/2020.12.22.423983
Abstract: The Pseudomonas putida group comprises strains with biotechnological and clinical relevance. P. alloputida was proposed as a new species and highlighted the misclassification of P. putida . Nevertheless, the population structure of P. alloputida remained unexplored. We retrieved 11,025 Pseudomonas genomes and used P. alloputida Kh7 T to delineate the species. The P. alloputida population structure comprises at least 7 clonal complexes (CCs). Clinical isolates are mainly found in CC4 and acquired resistance genes are present at low frequency in plasmids. Virulence profiles support the potential of CC7 members to outcompete other plant or human pathogens through a type VI secretion system. Finally, we found that horizontal gene transfer had an important role in shaping the ability of P. alloputida to bioremediate aromatic compounds such as toluene. Our results provide the grounds to understand P. alloputida genetic ersity and safety for environmental applications.
No related grants have been discovered for Glória Franco.