Biology subjects

D'Aurizio, R.

Publications and source records attributed to D'Aurizio, R..

5 recordsLinked to original sources

bioRxiv2024

MAPK15 Protects Against The Development Of Metabolic Dysfunction-Associated Steatotic Liver Disease

Accumulation of lipids in the liver characterizes metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disease worldwide. As liver injury progresses to metabolic dysfunction-associated steatohepatitis (MASH), MASLD can predispose individuals to cirrhosis and hepatocellular carcinoma. Here, we characterized the first knockout mouse model for mitogen-activated protein kinase 15 (MAPK15) and revealed its critical role in controlling lipid homeostasis in the liver. Indeed, Mapk15-/- mice exhibited a MASLD-like phenotype, and hepatocellular models allowed us to demonstrate that dysregulated accumulation of lipids was due to increased expression and membrane localization of the CD36 fatty acid translocase. Consistently, Mapk15-/- mice exhibited elevated hepatic levels of CD36 and feeding them with a western-type diet significantly accelerated their progression to a MASH-like phenotype. Ultimately, transcriptomic analysis of human cohorts revealed increased liver expression of MAPK15 in MASLD patients, compared to unaffected individuals, ultimately supporting a protective role for MAPK15 against this disease. Overall, our data highlight a critical role for MAPK15 in liver physiopathology, by contributing to maintain physiological intracellular levels of lipids in this tissue.

cell biology↗

bioRxiv2024

PoreMeth2: decoding the evolution of methylome alterations with Nanopore sequencing

In epigenetic analysis, identifying differentially methylated regions (DMRs) typically involves detecting groups of consecutive CpGs that show significant changes in their average methylation levels. However, the methylation state of a genomic region can also be characterized by a mixture of patterns (epialleles) with variable frequencies, and the relative proportions of such patterns can provide insights into its mechanisms of formation. Traditional methods based on bisulfite conversion and NGS, due to the read size (150 bp), allow epiallele frequency analysis only in high-CpG-density regions, limiting differential methylation studies to just 50% of the human methylome. Nanopore sequencing, with its long reads, enables the analysis of epiallele frequency across both high- and low-CpG-density regions. We introduce a novel computational approach, PoreMeth2, an R library that integrates epiallelic diversity and methylation frequency changes from Nanopore data to identify DMRs, assess their formation mechanisms, and annotate them to genic and regulatory elements. We applied PoreMeth2 to cancer and glial cell datasets, demonstrating its ability to distinguish epigenomic changes with a strong effect on gene expression from those with a weaker impact on transcriptional activity. PoreMeth2 is publicly available at https://github.com/Lab-CoMBINE/PoreMeth2.

bioinformatics↗

bioRxiv2024

Efficient and effective identification of cancer neoantigens from tumor only RNA-seq

The growing accessibility of sequencing experiments has significantly accelerated the development of personalized immunotherapies based on the identification of cancer neoantigens. Still, the prediction of neoantigens involves lengthy and inefficient protocols, requiring simultaneous analysis of sequencing data from paired tumor/normal exomes and tumor transcriptome, often resulting in a low success rate. To date, the feasibility of adopting a more efficient strategy has not been fully evaluated. To this end, we developed ENEO, a computational approach to detect cancer neoantigens using solely the tumor RNA-seq data while addressing the lack of matched control through a Bayesian probabilistic model. ENEO was assessed on TESLA benchmark dataset, reporting efficient identification of DNA-alterations derived neoantigens and compelling results against state-of-art exome-based methods. We further validated the method on two independent cohorts, encompassing different tumor types and experimental procedures. Our work demonstrates that a tumor-only RNA-based approach, such as the one implemented in ENEO, maintains accuracy in identifying mutated peptides resulting from expressed genomic alterations, while also broadening the pool of potential pMHCs with RNAspecific mutations in a faster and cost-effective way. ENEO is freely available at https://github.com/ctglab/ENEO

bioinformatics↗

bioRxiv2022

Bridging between mouse and human enhancer-promoter long-range interactions in neural stem cells, to understand enhancer function in neurodevelopmental disease

Non-coding variation in complex human disease has been well established by genome-wide association studies, and it is thought to involve regulatory elements, such as enhancers, whose variation affects the expression of the gene responsible for the disease. The regulatory elements often lie far from the gene they regulate, or within introns of genes differing from the regulated gene, making it difficult to identify the gene whose function is affected by a given enhancer variation. Enhancers are connected to their target gene promoters via long-range physical interactions (loops). In our study, we re-mapped, onto the human genome, more than 10,000 enhancers connected to promoters via long-range interactions, that we had previously identified in mouse brain-derived neural stem cells by RNApolII-ChIA-PET analysis, coupled to ChIP-seq mapping of DNA/chromatin regions carrying epigenetic enhancer marks. These interactions are thought to be functionally relevant. We discovered, in the human genome, thousands of DNA regions syntenic with the interacting mouse DNA regions (enhancers+connected promoters). We further annotated these human regions regarding their overlap with sequence variants (single nucleotide polymorphisms, SNPs; copy number variants, CNVs), that were previously associated with neurodevelopmental disease in human. We document various cases in which the genetic variant, associated in human to neurodevelopmental disease, affects an enhancer involved in long-range interactions: SNPs, previously identified by genome-wide association studies to be associated with schizophrenia, bipolar disorder, and intelligence, are located within our human syntenic enhancers, and alter transcription factors recognition sites. Similarly, CNVs associated to autism spectrum disease and other neurodevelopmental disorders overlap with our human syntenic enhancers. Some of these enhancers are connected (in mouse) to homologs of genes already associated to the human disease, strengthening the hypothesis that the gene is indeed involved in the disease. Other enhancers are connected to genes not previously associated with the disease, pointing to their possible pathogenetic involvement. Our observations provide a resource for further exploration of neural disease, in parallel with the now widespread genome-wide identification of DNA variants in patients with neural disease.

neuroscience↗

bioRxiv2017

The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito

Gene drives have enormous potential for the control of insect populations of medical and agricultural relevance. By preferentially biasing their own inheritance gene drives can rapidly introduce genetic traits even if these confer a negative fitness on the population.\n\nWe have recently developed gene drives based on a CRISPR nuclease construct that is designed to disrupt key genes essential for female fertility in the malaria mosquito. The construct copies itself and the associated genetic disruption from one homologous chromosome to another during gamete formation, in a process called homing that ensures the majority of offspring inherit the drive. Such drives have the potential to cause long-lasting, sustainable population suppression though they are also expected to impose a large selection pressure for resistance in the mosquito. One of these population suppression gene drives showed rapid invasion of a caged population over 4 generations, establishing proof of principle for this technology. In order to assess the potential for the emergence of resistance to the gene drive in this population we allowed it to run for 25 generations and monitored the frequency of the gene drive over time. Following the initial increase of the gene drive we noticed a gradual decrease in its frequency that was accompanied emergence of small, nuclease-induced mutations at the target gene that are resistant to further cleavage and restore its functionality. Such mutations show rates of increase consistent with positive selection in the face of the gene drive. Our findings represent the first documented example of selection for resistance to a synthetic gene drive and lead to important design recommendations and considerations in order to mitigate for resistance for future gene drive applications.

evolutionary biology↗