Nuova ricerca


Assegnista di ricerca presso: Dipartimento di Scienze della Vita sede ex-Scienze Biomediche

Home |


2020 - Computational Methods for the Integrative Analysis of Genomics and Pharmacological Data [Articolo su rivista]
Caroli, J.; Dori, M.; Bicciato, S.

Since the pioneering NCI-60 panel of the late'80's, several major screenings of genetic profiling and drug testing in cancer cell lines have been conducted to investigate how genetic backgrounds and transcriptional patterns shape cancer's response to therapy and to identify disease-specific genes associated with drug response. Historically, pharmacogenomics screenings have been largely heterogeneous in terms of investigated cell lines, assay technologies, number of compounds, type and quality of genomic data, and methods for their computational analysis. The analysis of this enormous and heterogeneous amount of data required the development of computational methods for the integration of genomic profiles with drug responses across multiple screenings. Here, we will review the computational tools that have been developed to integrate cancer cell lines' genomic profiles and sensitivity to small molecule perturbations obtained from different screenings.

2019 - Integration of bioinformatic predictions and experimental data to identify circRNA-miRNA associations [Articolo su rivista]
Dori, M.; Bicciato, S.

Circular RNAs (circRNAs) have recently emerged as a novel class of transcripts, characterized by covalently linked 3′–5′ ends that result in the so-called backsplice junction. During the last few years, thousands of circRNAs have been identified in different organisms. Yet, despite their role as disease biomarker started to emerge, depicting their function remains challenging. Different studies have shown that certain circRNAs act as miRNA sponges, but any attempt to generalize from the single case to the “circ-ome” has failed so far. In this review, we explore the potential to define miRNA “sponging” as a more general function of circRNAs and describe the different approaches to predict miRNA response elements (MREs) in known or novel circRNA sequences. Moreover, we discuss how experiments based on Ago2-IP and experimentally validated miRNA:target duplexes can be used to either prioritize or validate putative miRNA-circRNA associations.

2016 - Association of CFHR1 homozygous deletion with acute myelogenous leukemia in the European population [Articolo su rivista]
Fratelli, Maddalena; Bolis, Marco; Kurosaki, Mami; Dori, Martina; Guarnaccia, Valeria; Spinelli, Orietta; Alberti, Marta; Valoti, Elisabetta; Pileggi, Silvana; Noris, Marina; Remuzzi, Giuseppe; Rambaldi, Alessandro; Terao, Mineko; Garattini, Enrico

Our data demonstrate an association between the germinal homozygous deletion of the CFHR1 gene and acute myeloid leukemia (AML) in the Caucasian population. The frequency of this deletion is 4 % in the healthy reference and the medulloblastoma populations, while it is 7 % in AML patients. The study may define a novel subtype of AML, with a peculiar etio-pathogenesis related to alterations of the complement factor cascade.

2014 - MicroRNAs Establish Robustness and Adaptability of a Critical Gene Network to Regulate Progenitor Fate Decisions during Cortical Neurogenesis [Articolo su rivista]
Ghosh, Tanay; Aprea, Julieta; Nardelli, Jeannette; Engel, Hannes; Selinger, Christian; Mombereau, Cedric; Lemonnier, Thomas; Moutkine, Imane; Schwendimann, Leslie; Dori, Martina; Irinopoulou, Theano; Henrion-Caude, Alexandra; Benecke, Arndt G.; Arnold, Sebastian J.; Gressens, Pierre; Calegari, Federico; Groszer, Matthias

Over the course of cortical neurogenesis, the transition of progenitors from proliferation to differentiation requires a precise regulation of involved gene networks under varying environmental conditions. In order to identify such regulatory mechanisms, we analyzed microRNA (miRNA) target networks in progenitors during early and late stages of neurogenesis. We found that cyclin D1 is a network hub whose expression is miRNA-dosage sensitive. Experimental validation revealed a feedback regulation between cyclin D1 and its regulating miRNAs miR-20a, miR-20b, and miR-23a. Cyclin D1 induces expression of miR-20a and miR-20b, whereas it represses miR-23a. Inhibition of any of these miRNAs increases the developmental stage-specific mean and dynamic expression range (variance) of cyclin D1 protein in progenitors, leading to reduced neuronal differentiation. Thus, miRNAs establish robustness and stage-specific adaptability to a critical dosage-sensitive gene network during cortical neurogenesis. Understanding such network regulatory mechanisms for key developmental events can provide insights into individual susceptibilities for genetically complex neuropsychiatric disorders. © 2014 The Authors.

2014 - Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers [Articolo su rivista]
Cottini, Francesca; Hideshima, Teru; Xu, Chunxiao; Sattler, Martin; Dori, Martina; Agnelli, Luca; Ten Hacken, Elisa; Bertilaccio, Maria Teresa; Antonini, Elena; Neri, Antonino; Ponzoni, Maurilio; Marcatti, Magda; Richardson, Paul G; Carrasco, Ruben; Kimmelman, Alec C; Wong, Kwok-Kin; Caligaris-Cappio, Federico; Blandino, Giovanni; Kuehl, W Michael; Anderson, Kenneth C; Tonon, Giovanni

Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine-threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels. © 2014 Nature America, Inc. All rights reserved.

2013 - Transcriptome sequencing during mouse brain development identifies long non-coding RNAs functionally involved in neurogenic commitment [Articolo su rivista]
Aprea, Julieta; Prenninger, Silvia; Dori, Martina; Ghosh, Tanay; Monasor, Laura Sebastian; Wessendorf, Elke; Zocher, Sara; Massalini, Simone; Alexopoulou, Dimitra; Lesche, Mathias; Dahl, Andreas; Groszer, Matthias; Hiller, Michael; Calegari, Federico

Transcriptome analysis of somatic stem cells and their progeny is fundamental to identify new factors controlling proliferation versus differentiation during tissue formation. Here, we generated a combinatorial, fluorescent reporter mouse line to isolate proliferating neural stem cells, differentiating progenitors and newborn neurons that coexist as intermingled cell populations during brain development. Transcriptome sequencing revealed numerous novel long non-coding (lnc)RNAs and uncharacterized protein-coding transcripts identifying the signature of neurogenic commitment. Importantly, most lncRNAs overlapped neurogenic genes and shared with them a nearly identical expression pattern suggesting that lncRNAs control corticogenesis by tuning the expression of nearby cell fate determinants. We assessed the power of our approach by manipulating lncRNAs and protein-coding transcripts with no function in corticogenesis reported to date. This led to several evident phenotypes in neurogenic commitment and neuronal survival, indicating that our study provides a remarkably high number of uncharacterized transcripts with hitherto unsuspected roles in brain development. Finally, we focussed on one lncRNA, Miat, whose manipulation was found to trigger pleiotropic effects on brain development and aberrant splicing of Wnt7b. Hence, our study suggests that lncRNA-mediated alternative splicing of cell fate determinants controls stem-cell commitment during neurogenesis. © 2013 European Molecular Biology Organization.