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Browsing by Author "Matullo, Giuseppe"
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Item Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging(Cell Press, 2019-09-05) Flex, Elisabetta; Martinelli, Simone; Van Dijck, Anke; Ciolfi, Andrea; Cecchetti, Serena; Coluzzi, Elisa; Pannone, Luca; Andreoli, Cristina; Radio, Francesca Clementina; Pizzi, Simone; Carpentieri, Giovanna; Bruselles, Alessandro; Catanzaro, Giuseppina; Pedace, Lucia; Miele, Evelina; Carcarino, Elena; Ge, Xiaoyan; Chijiwa, Chieko; Lewis, M.E. Suzanne; Meuwissen, Marije; Kenis, Sandra; Van der Aa, Nathalie; Larson, Austin; Brown, Kathleen; Wasserstein, Melissa P.; Skotko, Brian G.; Begtrup, Amber; Person, Richard; Karayiorgou, Maria; Roos, J. Louw; Van Gassen, Koen L.; Koopmans, Marije; Bijlsma, Emilia K.; Santen, Gijs W.E.; Barge-Schaapveld, Daniela Q.C.M.; Ruivenkamp, Claudia A.L.; Hoffer, Mariette J.V.; Lalani, Seema R.; Streff, Haley; Craigen, William J.; Graham, Brett H.; van den Elzen, Annette P.M.; Kamphuis, Daan J.; Ounap, Katrin; Reinson, Karit; Pajusalu, Sander; Wojcik, Monica H.; Viberti, Clara; Di Gaetano, Cornelia; Bertini, Enrico; Petrucci, Simona; De Luca, Alessandro; Rota, Rossella; Ferretti, Elisabetta; Matullo, Giuseppe; Dallapiccola, Bruno; Sgura, Antonella; Walkiewicz, Magdalena; Kooy, R. Frank; Tartaglia, Marco; Medical and Molecular Genetics, School of MedicineHistones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.Item Extracellular vesicles derived from tumour cells as a trigger of energy crisis in the skeletal muscle(Wiley, 2022) Pin, Fabrizio; Beltrà, Marc; Garcia-Castillo, Lorena; Pardini, Barbara; Birolo, Giovanni; Matullo, Giuseppe; Penna, Fabio; Guttridge, Denis; Costelli, Paola; Anatomy, Cell Biology and Physiology, School of MedicineBackground: Cachexia, a syndrome frequently occurring in cancer patients, is characterized by muscle wasting, altered energy and protein metabolism and impaired myogenesis. Tumour-derived microvesicles (TMVs) containing proteins, messenger RNAs (mRNAs), and non-coding RNAs could contribute to cancer-induced muscle wasting. Methods: Differential ultracentrifugation was used to isolate TMVs from the conditioned medium of Lewis lung carcinoma and C26 colon carcinoma cell cultures. TMVs were added to the culture medium of C2C12 myoblasts and myotubes for 24-48-72 h, and the effects on protein and energy metabolism were assessed. TMVs were also isolated from the blood of C26-bearing mice. MicroRNA (miR) profile of TMVs was obtained by RNA-seq and validated by digital drop PCR. Selected miRs were overexpressed in C2C12 myoblasts to assess the effects on myogenic differentiation. Results: Differentiation was delayed in C2C12 myoblasts exposed to TMVs, according to reduced expression of myosin heavy chain (MyHC; about 62% of controls at Day 4) and myogenin (about 68% of controls at Day 4). As for myotubes, TMVs did not affect the expression of MyHC, while revealed able to modulate mitochondria and oxidative metabolism. Indeed, reduced mRNA levels of PGC-1α (C = 1 ± 0.2, TMV = 0.57 ± 0.06, normalized fold change, P < 0.05) and Cytochrome C (C = 1 ± 0.2, TMV = 0.65 ± 0.04, normalized fold change, P < 0.05), associated with increased BNIP3 expression (C = 1 ± 0.1, TMV = 1.29 ± 0.2, normalized fold change, P < 0.05), were observed, suggesting reduced mitochondrial biogenesis/amount and enhanced mitophagy. These changes were paralleled by decreased oxygen consumption (C = 686.9 ± 44 pmol/min, TMV = 552.25 ± 24 pmol/min, P < 0.01) and increased lactate levels (C = 0.0063 ± 0.00045 nmol/μL, TMV = 0.0094 ± 0.00087 nmol/μL, P < 0.01). A total of 118 miRs were found in MVs derived from the plasma of the C26 hosts; however, only three of them were down-regulated (RNA-seq): miR-181a-5p (-1.46 fold change), miR-375-3p (-2.52 fold change), and miR-455-5p (-3.87 fold change). No correlation could be observed among miRs in the MVs obtained from the blood of the C26 host and those released by C26 cells in the culture medium. Overexpression of miR-148a-3p and miR-181a-5p in C2C12 myoblasts revealed the ability to impinge on the mRNA levels of Myf5, Myog, and MyHC (Myh4 and Myh7). Conclusions: These results show that in C2C12 cultures, TMVs are able to affect both differentiation and the mitochondrial system. Such effects could be related to TMV-contained miRs.Item Plasma microRNAs as biomarkers of pancreatic cancer risk in a prospective cohort study(Wiley, 2017-09-01) Duell, Eric J.; Lujan-Barroso, Leila; Sala, Nuria; McElyea, Samantha Deitz; Overvad, Kim; Tjonneland, Anne; Olsen, Anja; Weiderpass, Elisabete; Busund, Lill-Tove; Moi, Line; Muller, David; Vineis, Paolo; Aune, Dagfinn; Matullo, Giuseppe; Naccarati, Alessio; Panico, Salvatore; Tagliabue, Giovanna; Tumino, Rosario; Palli, Domenico; Kaaks, Rudolf; Katzke, Verena A.; Boeing, Heiner; H.B.(as), Bueno-de-Mesquita; Peeters, Petra H.; Trichopoulou, Antonia; Lagiou, Pagona; Kotanidou, Anastasia; Travis, Ruth C.; Wareham, Nick; Khaw, Kay-Tee; Quiros, Jose Ramon; Rodriguez-Barranco, Miguel; Dorronsoro, Miren; Chirlaque, Maria-Dolores; Ardanaz, Eva; Severi, Gianluca; Boutron-Rault, Marie-Christine; Rebours, Vinciane; Brennan, Paul; Gunter, Marc; Scelo, Ghislaine; Cote, Greg; Sherman, Stuart; Korc, Murray; Medicine, School of MedicineNoninvasive biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis and disease risk stratification are greatly needed. We conducted a nested case-control study within the Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate prediagnostic microRNAs (miRs) as biomarkers of subsequent PDAC risk. A panel of eight miRs (miR-10a, -10b, -21-3p, -21-5p, -30c, -106b, -155 and -212) based on previous evidence from our group was evaluated in 225 microscopically confirmed PDAC cases and 225 controls matched on center, sex, fasting status and age/date/time of blood collection. MiR levels in prediagnostic plasma samples were determined by quantitative RT-PCR. Logistic regression was used to model levels and PDAC risk, adjusting for covariates and to estimate area under the receiver operating characteristic curves (AUC). Plasma miR-10b, -21-5p, -30c and -106b levels were significantly higher in cases diagnosed within 2 years of blood collection compared to matched controls (all p-values <0.04). Based on adjusted logistic regression models, levels for six miRs (miR-10a, -10b, -21-5p, -30c, -155 and -212) overall, and for four miRs (-10a, -10b, -21-5p and -30c) at shorter follow-up time between blood collection and diagnosis (≤5 yr, ≤2 yr), were statistically significantly associated with risk. A score based on the panel showed a linear dose-response trend with risk (p-value = 0.0006). For shorter follow-up (≤5 yr), AUC for the score was 0.73, and for individual miRs ranged from 0.73 (miR-212) to 0.79 (miR-21-5p).