Biology subjects

Colombo, F.

Publications and source records attributed to Colombo, F..

4 recordsLinked to original sources

bioRxiv2022

Extracellular Vesicle exchange is favored by cell proximity.

Extracellular vesicles (EVs) are biological nanovectors that retain information of the cell of origin and convey signals to recipient cells. Therefore, EVs are ideal platforms for the development of diagnostic tools and of bio-inspired drug delivery technologies. However, the dynamics of EV distribution in physiological conditions are still underexplored. Using an elegant series of experiments, including quantitative assays to define EV transfer and five dimension live cell imaging, we observe the release and internalization of EVs in real time and we demonstrate that EVs are mainly exchanged at the cell-cell interface. These observations prompt paradigm shifting consequences: first, EVs are mostly short-range intercellular vectors that influence adjacent cells; second, our data explain why increases in the internal pressure and permeability of the parenchyma, two hallmarks of inflammation and cancer, can facilitate EV escape from the damaged tissue. In conclusion, we provide experimental evidence supporting why EVs have great potential for the implementation of specific and sensitive liquid biopsy tests.

cell biology↗

bioRxiv2022

Gut microbiota composition in colorectal cancer patients is genetically regulated

The risk of colorectal cancer (CRC) depends on environmental and genetic factors. Among environmental factors, an imbalance in the gut microbiota can increase CRC risk. Also, microbiota is influenced by host genetics. However, it is not known if germline variants influence CRC development by modulating microbiota composition. We investigated germline variants associated with the abundance of bacterial populations in the normal (non-involved) colorectal mucosa of 93 CRC patients and evaluated their possible role in disease. Using a multivariable linear regression, we assessed the association between germline variants identified by genome wide genotyping and bacteria abundances determined by 16S rRNA gene sequencing. We identified 37 germline variants associated with the abundance of the genera Bacteroides, Ruminococcus, Akkermansia, Faecalibacterium and Gemmiger and with alpha diversity. These variants are correlated with the expression of 58 genes involved in inflammatory responses, cell adhesion, apoptosis and barrier integrity. Genes and bacteria appear to be involved in the same processes. In fact, expression of the pro-inflammatory genes GAL, GSDMD and LY6H was correlated with the abundance of Bacteroides, which has pro-inflammatory properties; abundance of the anti-inflammatory genus Faecalibacterium correlated with expression of KAZN, with barrier-enhancing functions. Both the microbiota composition and local inflammation are regulated, at least partially, by the same germline variants. These variants may regulate the microenvironment in which bacteria grow and predispose to the development of cancer. Identification of these variants is the first step to identifying higher-risk individuals and proposing tailored preventive treatments that increase beneficial bacterial populations. Authors summaryGenetic variants describe the variation in the DNA sequence in our genomes and are unique for each person. These variants modify the risk of developing colorectal cancer (CRC) by regulating genes that participate in CRC-associated mechanisms. CRC risk is also affected by microbiota (the microorganisms residing in ourselves). A balanced microbiota helps perform our normal body functions, but can induce cancer, if this balance is lost. Microbiota is affected by factors such as pollution and diet, but is also regulated by genetic variants. However, can genetic variants predispose to cancer risk by regulating microbiota? To answer this question, we sequenced the genetic variants of 93 CRC patients and examined the composition of their intestinal microbiota. We identified variants that regulate the presence of benefic or pathogenic bacteria. The same variants also affect the expression of genes that participate in inflammation, immunity and integrity of intestinal tissue. We found that genetic variants regulate gene expression and microbiota at the same time, predisposing to a higher or lower CRC risk. People with variants predisposing to a higher risk may be benefitted by tailored preventive treatments that increase beneficial bacteria.

genetics↗

bioRxiv2020

First responders shape a prompt and sharp NF-Bκ-mediated transcriptional response to TNF-α

SummaryNF-κB acts as the master regulator of the transcriptional response to inflammatory signals by translocating into the nucleus upon stimuli, but we lack a single-cell characterization of the resulting transcription dynamics. Here we show that transcription of NF-κB target genes is strongly heterogeneous in individual cells but dynamically coordinated at the population level, since the average nascent transcription is prompt (i.e. occurs almost immediately) and sharp (i.e. increases and decreases rapidly) compared to NF-κB nuclear localization. Using an NF-κB-controlled MS2 reporter we confirm that the population-level transcriptional activity emerges from a strongly heterogeneous response in single cells as compared to NF-κB translocation dynamics, including the presence of a fraction of “first responders”. Mathematical models show that a combination of NF-κB mediated gene activation and a gene activity module including a gene refractory state is enough to produce sharp and prompt transcriptional responses. Our data and models show how the expression of the target genes of a paradigmatic inducible transcription activator upon stimuli can be time-resolved at population level and yet heterogeneous across single cells.Competing Interest StatementThe authors have declared no competing interest.View Full Text

systems biology↗

bioRxiv2020

Lung expression of genes encoding SARS-CoV-2 cell entry molecules and antiviral restriction factors: interindividual differences are associated with age and germline variants

Germline variants in genes involved in SARS-CoV-2 cell entry (i.e. ACE2 and TMPRSS2) may influence the susceptibility to infection, as may polymorphisms in genes involved in the innate host response to viruses (e.g. APOBEC3 family). We searched for polymorphisms acting, in lung tissue, as expression quantitative trait loci (eQTLs) for 15 candidate COVID-19 susceptibility genes, selected for their roles in virus cell entry and host antiviral responses. No significant eQTLs were identified for ACE2 and TMPRSS2 genes, whose expression levels did not associate with either sex or age of the 408 patients whose non-diseased lung tissue was analyzed. Instead, we identified seven cis-eQTLs (FDR<0.05) for APOBEC3D and APOBEC3G (rs139296, rs9611092, rs139331, rs8177832, rs17537581, rs61362448, and rs738469). The genetic control of the expression of APOBEC3 genes, which encode enzymes that interfere with virus replication, may explain interindividual differences in risk or severity of viral infections. Future studies should investigate the role of host genetics in COVID-19 patients using a genome-wide approach, to identify other genes whose expression levels are associated with susceptibility to SARS-CoV-2 infection or COVID-19 severity. Author summaryIdentification of expression quantitative trait loci (eQTLs) has become commonplace in functional studies on the role of individual genetic variants in susceptibility to diseases. In COVID-19, it has been proposed that individual variants in SARS-CoV-2 cell entry and innate host response genes may influence the susceptibility to infection. We searched for polymorphisms acting, in non-diseased lung tissue of 408 patients, as eQTLs for 15 candidate COVID-19 susceptibility genes, selected for their roles in virus cell entry and host antiviral responses. Seven cis-eQTLs were detected for APOBEC3D and APOBEC3G genes, which encode enzymes that interfere with virus replication. No significant eQTLs were identified for ACE2 and TMPRSS2 genes. Therefore, the identified eQTLs may represent candidate loci modulating interindividual differences in risk or severity of SARS-CoV-2 virus infection.

genomics↗