Yari Ciribilli
e-mail: ciribilli AT science.unitn.it
affiliation: Università di Trento
research area(s): Genetics And Genomics
Course:
Biomolecular Sciences
University/Istitution: Università di Trento
University/Istitution: Università di Trento
EDUCATIONAL STUDIES:
• August 1996: General Certificate of Education at “Leonardo da Vinci” Scientific High School of Genoa
• 1 October 1996 – 20 February 2002: University Degree “cum laudae” in Biological Science at University of Genoa (Thesis title: Characterization of the dominant negative potential of mutants of the tumor suppressor gene p53 using a yeast-based assay – Advisors: Prof. A. Abbondandolo, Dr. G. Fronza)
• 16 June 2002: Professional qualification of Biologist
• 1 January 2006 – 31 December 2008: PhD program student (XXI° Cycle) in Oncological Genetics and Biology of Differentiation at Biomedical Science and Technology School - University of Genoa; (Project title: Transcriptional cooperation between p53 and Estrogen Receptors at a polymorphic variant of the VEGFR-1 (Flt-1) promoter – Tutors: Dr. A. Inga and Dr. G. Fronza)
PROFESSIONAL EXPERIENCES:
• 1 October 2000 - 20 February 2002: Undergraduate Internship for the preparation of the experimental thesis, Mutagenesis Laboratory of National Institute for Cancer Research (IST), Genoa, Italy
• 10 April 2002 – 10 June 2002: Collaboration with the same Laboratory due to an assignment of a temporary researcher position
• July 2002 – 31 December 2002: Collaboration with the same Laboratory as junior researcher
• 1 January 2003 – 31 December 2005: Graduate Fellow, Mutagenesis Laboratory of National Institute for Cancer Research (IST), Genoa, Italy, winner of a National Fellowship issued by Italian Foundation for Cancer Research (FIRC)
• 1 January 2006 – 31 December 2008: PhD program (XXI° Cycle) in Oncological Genetics and Biology of Differentiation at Biomedical Science and Technology School - University of Genoa, winner of a Fellowship issued by University of Genoa, Italy
• 16 April 2007 – 9 July 2007: Visiting Fellow during the PhD program at Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM) – Hannover, Germany
• 04 February 2008 – to 26 May 2008: Visiting Fellow during the PhD program at Laboratory of Transcriptional Networks, Centre for Integrative Biology (CIBIO) - University of Trento, Italy
• 16 June 2008 – 30 September 2008: Visiting Fellow during the PhD program at Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM) – Hannover, Germany
• 1 October 2008 – 5 December 2008: Visiting Fellow during the PhD program at Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM) – Biopark, Regensburg, Germany
• 1 January 2009 – 16 February 2009: Visiting fellow at Laboratory of Transcriptional Networks, Centre for Integrative Biology (CIBIO) - University of Trento, Italy
• 17 February 2009 – 30 April 2009: PostDoc fellow at Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM) – Biopark, Regensburg, Germany
• 1 May 2009 – 31 May 2009: PostDoc fellow at Laboratory of Transcriptional Networks, Centre for Integrative Biology (CIBIO) - University of Trento, Italy
• 1 June 2009 to 30 April 2010: Researcher fellow, Molecular Mutagenesis and DNA Repair Laboratory at National Institute for Cancer Research (IST), Genoa, Italy
• 1 May 2010 – to date: Marie Curie Action – PAT PostDoc fellow at Laboratory of Transcriptional Networks, Centre for Integrative Biology (CIBIO) - University of Trento, Italy
• Spring 2010: Assignment of a assistant teaching position (for the academic year 2009-2010) in Laboratory of Genetics, Biomolecular Sciences and Technology, University of Trento, Italy
• Autumn 2010: Assignment of a assistant teaching position (for the academic year 2010-2011) in Laboratory of Genetics, Biomolecular Sciences and Technology, University of Trento, Italy
• August 1996: General Certificate of Education at “Leonardo da Vinci” Scientific High School of Genoa
• 1 October 1996 – 20 February 2002: University Degree “cum laudae” in Biological Science at University of Genoa (Thesis title: Characterization of the dominant negative potential of mutants of the tumor suppressor gene p53 using a yeast-based assay – Advisors: Prof. A. Abbondandolo, Dr. G. Fronza)
• 16 June 2002: Professional qualification of Biologist
• 1 January 2006 – 31 December 2008: PhD program student (XXI° Cycle) in Oncological Genetics and Biology of Differentiation at Biomedical Science and Technology School - University of Genoa; (Project title: Transcriptional cooperation between p53 and Estrogen Receptors at a polymorphic variant of the VEGFR-1 (Flt-1) promoter – Tutors: Dr. A. Inga and Dr. G. Fronza)
PROFESSIONAL EXPERIENCES:
• 1 October 2000 - 20 February 2002: Undergraduate Internship for the preparation of the experimental thesis, Mutagenesis Laboratory of National Institute for Cancer Research (IST), Genoa, Italy
• 10 April 2002 – 10 June 2002: Collaboration with the same Laboratory due to an assignment of a temporary researcher position
• July 2002 – 31 December 2002: Collaboration with the same Laboratory as junior researcher
• 1 January 2003 – 31 December 2005: Graduate Fellow, Mutagenesis Laboratory of National Institute for Cancer Research (IST), Genoa, Italy, winner of a National Fellowship issued by Italian Foundation for Cancer Research (FIRC)
• 1 January 2006 – 31 December 2008: PhD program (XXI° Cycle) in Oncological Genetics and Biology of Differentiation at Biomedical Science and Technology School - University of Genoa, winner of a Fellowship issued by University of Genoa, Italy
• 16 April 2007 – 9 July 2007: Visiting Fellow during the PhD program at Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM) – Hannover, Germany
• 04 February 2008 – to 26 May 2008: Visiting Fellow during the PhD program at Laboratory of Transcriptional Networks, Centre for Integrative Biology (CIBIO) - University of Trento, Italy
• 16 June 2008 – 30 September 2008: Visiting Fellow during the PhD program at Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM) – Hannover, Germany
• 1 October 2008 – 5 December 2008: Visiting Fellow during the PhD program at Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM) – Biopark, Regensburg, Germany
• 1 January 2009 – 16 February 2009: Visiting fellow at Laboratory of Transcriptional Networks, Centre for Integrative Biology (CIBIO) - University of Trento, Italy
• 17 February 2009 – 30 April 2009: PostDoc fellow at Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM) – Biopark, Regensburg, Germany
• 1 May 2009 – 31 May 2009: PostDoc fellow at Laboratory of Transcriptional Networks, Centre for Integrative Biology (CIBIO) - University of Trento, Italy
• 1 June 2009 to 30 April 2010: Researcher fellow, Molecular Mutagenesis and DNA Repair Laboratory at National Institute for Cancer Research (IST), Genoa, Italy
• 1 May 2010 – to date: Marie Curie Action – PAT PostDoc fellow at Laboratory of Transcriptional Networks, Centre for Integrative Biology (CIBIO) - University of Trento, Italy
• Spring 2010: Assignment of a assistant teaching position (for the academic year 2009-2010) in Laboratory of Genetics, Biomolecular Sciences and Technology, University of Trento, Italy
• Autumn 2010: Assignment of a assistant teaching position (for the academic year 2010-2011) in Laboratory of Genetics, Biomolecular Sciences and Technology, University of Trento, Italy
Our group focuses on the analysis of transcriptional network of stress responses, with an emphasis on sequence-specific transcription factors (TFs) that are involved in tumorigenesis. In particular, we are addressing the role of response element (RE) sequences in modulating transactivation specificity and the functional consequences of disease-associated mutations in transcription and of single nucleotide polymorphisms (SNPs) in RE sequences.
Research directions
Our group uses assay systems based in the eukaryotic model organism S. cerevisiae, which we refer to as an “in vivo test-tube”, as well as human cell lines. Specific projects are:
* Transcriptional cooperation between the tumor suppressor p53 and the estrogen receptors. The study draws upon our recent identification of a SNP in the Flt1 promoter. We have established that the Flt1 gene can be the target of cooperative interaction between stress-activated p53 and ligand-bound ER, mediated by two sub-optimal REs, one of which contains a SNP. These results depict a novel level of functional interactions among ERs and p53 and establish that both proteins can act as sequence-specific TFs at non-canonical REs. This type of transcriptional regulation sets an important example where environmentally distinct agents (e.g., ER ligands and radiation) could create a synergistic response at a common target gene.
* CDKN2A/p16INK4a 5'UTR variants in melanoma predisposition: lost in translation, somewhere.The CDKN2A gene is the most common high penetrance susceptibility gene identified to date in melanoma families. Rare polymorphisms or sequence variants at the CDKN2A/ p16INK4a 5'UTR, encountered during routine screening, are usually defined as variants with unknown significance after determining their frequency in control population and the cosegregation analysis in the family, when possible. We recently developed Monocistronic as well as bicistronic luciferase reporter vectors to study a panel of p16INK4a 5'UTR variants identified as heterozygous changes in patients from a hospital-based series of melanoma cases (c.-21C>T; c.-25C>T&c.-180G>A; c.-56G>T; c.-67G>C). We also applied polysomal profiling to measure allelic imbalance in heterozygous, patient-derived cell lines. The c.-21C>T variant but also c.-56T>G and c.-67G>C exhibited lower association with the polysomes suggestive of reduced mRNA translation efficiency [Bisio et al, 2010]. Work is being now extended to a panel of eleven additional germline variants in the 5'UTR of p16INK4a and the functional assays are being tailored towards a mechanistic understanding of their impact on mRNA stability and translation potential. In particular we are focusing on the functional interactions between wild-type and variant p16INK4a 5'- and 3'-UTR sequences and on the impact the variants can have on the targeting ofp16INK4a mRNA by microRNAs and RBPs.
* p53-miR-dependent post-transcriptional circuits: mechanisms, targets and inter-individual variation. A direct role of p53 on the activation of microRNA expression as well as a role on selective maturation of microRNA precursors has been recently established. Using custom pattern search approaches, the laboratory directed by Dr. Jegga (Cincinnati Children’s Hospital and University of Cincinnati) has identified an additional group of candidate microRNAs for direct p53 transcriptional control. To validate p53 family-mediated control of these newly predicted target miRs we are investigating the potential for wild type p53, p63 and p73 to transactivate from p53 response elements (REs) mapped at the miR promoters. This is being developed through yeast- and mammalian cell-based reporter assay as well as RTqPCR and ChIP assays. Our study is beginning to reveal additional miRs that could be directly regulated by the p53-family of transcription factors and could contribute to the tuning of p53-induced responses with the possibility of inter-individual variations due to functional SNPs.
Research directions
Our group uses assay systems based in the eukaryotic model organism S. cerevisiae, which we refer to as an “in vivo test-tube”, as well as human cell lines. Specific projects are:
* Transcriptional cooperation between the tumor suppressor p53 and the estrogen receptors. The study draws upon our recent identification of a SNP in the Flt1 promoter. We have established that the Flt1 gene can be the target of cooperative interaction between stress-activated p53 and ligand-bound ER, mediated by two sub-optimal REs, one of which contains a SNP. These results depict a novel level of functional interactions among ERs and p53 and establish that both proteins can act as sequence-specific TFs at non-canonical REs. This type of transcriptional regulation sets an important example where environmentally distinct agents (e.g., ER ligands and radiation) could create a synergistic response at a common target gene.
* CDKN2A/p16INK4a 5'UTR variants in melanoma predisposition: lost in translation, somewhere.The CDKN2A gene is the most common high penetrance susceptibility gene identified to date in melanoma families. Rare polymorphisms or sequence variants at the CDKN2A/ p16INK4a 5'UTR, encountered during routine screening, are usually defined as variants with unknown significance after determining their frequency in control population and the cosegregation analysis in the family, when possible. We recently developed Monocistronic as well as bicistronic luciferase reporter vectors to study a panel of p16INK4a 5'UTR variants identified as heterozygous changes in patients from a hospital-based series of melanoma cases (c.-21C>T; c.-25C>T&c.-180G>A; c.-56G>T; c.-67G>C). We also applied polysomal profiling to measure allelic imbalance in heterozygous, patient-derived cell lines. The c.-21C>T variant but also c.-56T>G and c.-67G>C exhibited lower association with the polysomes suggestive of reduced mRNA translation efficiency [Bisio et al, 2010]. Work is being now extended to a panel of eleven additional germline variants in the 5'UTR of p16INK4a and the functional assays are being tailored towards a mechanistic understanding of their impact on mRNA stability and translation potential. In particular we are focusing on the functional interactions between wild-type and variant p16INK4a 5'- and 3'-UTR sequences and on the impact the variants can have on the targeting ofp16INK4a mRNA by microRNAs and RBPs.
* p53-miR-dependent post-transcriptional circuits: mechanisms, targets and inter-individual variation. A direct role of p53 on the activation of microRNA expression as well as a role on selective maturation of microRNA precursors has been recently established. Using custom pattern search approaches, the laboratory directed by Dr. Jegga (Cincinnati Children’s Hospital and University of Cincinnati) has identified an additional group of candidate microRNAs for direct p53 transcriptional control. To validate p53 family-mediated control of these newly predicted target miRs we are investigating the potential for wild type p53, p63 and p73 to transactivate from p53 response elements (REs) mapped at the miR promoters. This is being developed through yeast- and mammalian cell-based reporter assay as well as RTqPCR and ChIP assays. Our study is beginning to reveal additional miRs that could be directly regulated by the p53-family of transcription factors and could contribute to the tuning of p53-induced responses with the possibility of inter-individual variations due to functional SNPs.
1.Monti P.*, Ciribilli Y*, Jordan J, Menichini P., Umbach D.M., Resnick M.A., Luzzatto L., Inga A. and Fronza G. Functionality of germline p53 alleles influences clinical features. (2007). Clin. Cancer Research. 13: 3789-95. I.F.: 6,3
2.Cardellino U.*, Ciribilli Y*, Andreotti V. *, Modesto P., Menichini P., Fronza G., Pellegrino C. and Inga A. Transcriptional properties of feline p53 and its tumor-associated mutants: an yeast-based approach. (2007). Mutagenesis. 22: 417-23. I.F.: 2,4
3.Monti P*, Ciribilli Y*, Russo D, Bisio A, Perfumo C, Andreotti V, Menichini P, Inga A, Huang X, Gold B, Fronza G. Rev1 and Polzeta influence toxicity and mutagenicity of Me-lex, a sequence selective N3-adenine methylating agent. (2008) DNA Repair (Amst). 7(3):431-8. I.F.: 4,0
4.Reamon-Buettner SM, Ciribilli Y, Inga A and Borlak J. A loss-of-function mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts. (2008) Hum Mol Genet. 17(10):1397-405. I.F.: 7,8
5.Reamon-Buettner SM, Ciribilli Y, Traverso I, Kuhls B, Inga A and Borlak J. HAND1 mutations in septation defects of human hearts. (2009) Hum Mol Genet.. 18(19):3567-78. Epub 2009 Jul 7. I.F.: 7,8
6.Ciribilli Y*, Andreotti V*, Menendez D*, Schoenfelder G, Resnick MA and Inga A. Complex interplay between p53 and the Estrogen Receptors at a polymorphic variant of the VEGF receptor Flt-1 promoter. (2010) PlosOne. 5(4):e10236. I.F.: 5,0
7.Monti P., Perfumo C., Bisio A., Ciribilli Y., Menichini P., Russo D., Umbach D.M., Resnick M.A., Inga A. and Fronza G. Dominant-negative features of mutant p53 in germline carriers have limited impact on cancer outcomes. (2011) Mol. Cancer Res. 9(3):271-9. I.F.:
* This author contributed equally to this work
2.Cardellino U.*, Ciribilli Y*, Andreotti V. *, Modesto P., Menichini P., Fronza G., Pellegrino C. and Inga A. Transcriptional properties of feline p53 and its tumor-associated mutants: an yeast-based approach. (2007). Mutagenesis. 22: 417-23. I.F.: 2,4
3.Monti P*, Ciribilli Y*, Russo D, Bisio A, Perfumo C, Andreotti V, Menichini P, Inga A, Huang X, Gold B, Fronza G. Rev1 and Polzeta influence toxicity and mutagenicity of Me-lex, a sequence selective N3-adenine methylating agent. (2008) DNA Repair (Amst). 7(3):431-8. I.F.: 4,0
4.Reamon-Buettner SM, Ciribilli Y, Inga A and Borlak J. A loss-of-function mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts. (2008) Hum Mol Genet. 17(10):1397-405. I.F.: 7,8
5.Reamon-Buettner SM, Ciribilli Y, Traverso I, Kuhls B, Inga A and Borlak J. HAND1 mutations in septation defects of human hearts. (2009) Hum Mol Genet.. 18(19):3567-78. Epub 2009 Jul 7. I.F.: 7,8
6.Ciribilli Y*, Andreotti V*, Menendez D*, Schoenfelder G, Resnick MA and Inga A. Complex interplay between p53 and the Estrogen Receptors at a polymorphic variant of the VEGF receptor Flt-1 promoter. (2010) PlosOne. 5(4):e10236. I.F.: 5,0
7.Monti P., Perfumo C., Bisio A., Ciribilli Y., Menichini P., Russo D., Umbach D.M., Resnick M.A., Inga A. and Fronza G. Dominant-negative features of mutant p53 in germline carriers have limited impact on cancer outcomes. (2011) Mol. Cancer Res. 9(3):271-9. I.F.:
* This author contributed equally to this work
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