Dottorato in Genetica e Biologia Molecolare

Sapienza - Università di Roma

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Alessandro Fatica

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Alessandro Fatica

 

mail and telephone:

alessandro.fatica@uniroma1.it, 06-49912357

Lab Location:

Dept of Genetics and Molecular Biology, Ex-Istituto Fisiologia Generale (piano seminterrato).

Lab components:

Beatrice Salvatori, PhD student

Nkerorema Djodji Damas, undergraduate student

Arianna Mangiavacchi, undergraduate student

Research activity:

Role of microRNAs in myelopoiesis and acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy, characterized by complete or partial blockage at different stages of the differentiation of myeloid progenitor cells, which has been mainly attributed to chromosomal abnormalities. Our research interests are focused in defining the roles of microRNAs (miRNAs) in normal and abnormal differentiation of myeloid cells (granulocytes and monocytes). MiRNAs constitute a family of small non-coding RNAs that play important roles in post-transcriptional gene regulation. Given the extensive regulation of normal hematopoietic development by miRNA, it is not surprising that miRNAs are extensively involved in the pathogenesis of AML. A relevant number of human miRNAs have been shown to act as oncogenes or as tumor suppressor genes. The goals of our lab are to investigate the biology of these miRNAs, analyse their expression and understand their functions in normal and pathological conditions. In particular, we want to study how miRNAs can influence myelopoiesis and to identify their target mRNAs in order to understand the molecular networks involved in the alternative control between cell growth and differentiation.

Brief description of the project(s) available in the Lab for the XXVI cycle of the PhD course:

Several AML cell lines have been established over the years and used as suitable model systems to study the mechanisms of leukemogenesis. AML cell lines can be differentiated by specific pharmacological agents (e.g. ATRA and Vitamin D) in cells resembling normal myeloid cells. These agents activate transcriptional programs in which miRNAs play crucial roles by targeting hundreds of proteins thereby facilitating cell cycle arrest and changes required for differentiation. We have recently identified two miRNAs, miR-342 and miR-26a, induced during myeloid differentiation of AML cell lines. We showed that enforced expression of these miRNAs in AML cells attenuated proliferation and stimulated myeloid differentiation. It is thus important to understand how these miRNAs function by identifying their mRNA targets. This will be achieved by stable isotope labeling by amino acids in cell culture (SILAC). Although mRNA expression profiling can show changes based on miRNA activity, it is not always indicative of translation inhibition by a miRNA. On the other hand, protein analysis by mass spectrometry combined with SILAC has shown a strong correlation with miRNA activity. SILAC measures changes in the amount of newly synthesized proteins between two samples. This method relies upon the metabolic incorporation of "light" or "heavy" forms of the amino acid into the proteins to distinguish differences between such cell populations as normal and overexpressing the microRNAs by mass spectrometry analysis. Translational repression by specific miRNAs will be experimentally validated by standard luciferase assays. The second phase of the project will concern the manipulation (over-expression and suppression) of identified targets in AML cell lines and monitoring cellular pathways such us differentiation, cell replication and apoptosis.

Publications of the last 5 years:

1. Chiaretti S, Messina M, Tavolaro S, Zardo G, Elia L, Vitale A, Fatica A, Gorello P, Piciocchi A, Scappucci G, Bozzoni I, Fozza C, Candoni A, Guarini A, Foa' R. 2010. Gene expression profiling identifies a subset of adult T-cell acute lymphoblastic leukemia (T-ALL) with myeloid-like gene features and overexpression of miR-223. Haematologica. Apr 23. [Epub ahead of print]

2. Fatica A, Bozzoni I. 2009. Role of microRNAs in hematological malignancies. Expert Review of Hematology 2: 415-423.

3. Piacentini L, Fanti L, Negri R, Del Vescovo V, Fatica A, Altieri F, Pimpinelli S. 2009. Heterochromatin protein 1 (HP1a) positively regulates euchromatic gene expression through RNA transcript association and interaction with hnRNPs in Drosophila. PLoS Genet. 5: e1000670.

4. Starnes LM, Sorrentino A, Pelosi E, Ballarino M, Morsilli O, Biffoni M, Santoro S, Felli N, Castelli G, De Marchis ML, Mastroberardino G, Gabbianelli M, Fatica A, Bozzoni I, Nervi C, Peschle C. 2009. NFI-A directs the fate of hematopoietic progenitors to the erythroid or granulocytic lineage and controls beta-globin and G-CSF receptor expression. Blood 114: 1753-1763.

5. De Marchis M L , Ballarino M , Salvatori B, Puzzolo M C, Bozzoni I, Fatica A. 2009 A new molecular network comprising PU.1, interferon regulatory factor proteins and miR-342 stimulates ATRA-mediated granulocytic differentiation of acute promyelocytic leukemia cells. Leukemia, 23: 856-862.

6. Fatica A, Rosa A, Ballarino M, De Marchis ML, Rasmussen KD, Bozzoni I. 2008. Role of microRNAs in myeloid differentiation. Biochem Soc Trans. 36:1201-1205.

7. Sorrentino A, Ferracin M, Castelli G, Biffoni M, Tomaselli G, Baiocchi M, Fatica A, Negrini M, Peschle C, Valtieri M. 2008. Molecular and functional characterization of homogeneous multipotent mesenchymal stem cells. Exp. Hematol., 36: 1035-1046.

8. Rosa A, Ballarino M, Sorrentino A, Sthandier O, De Angelis FG, Marchioni M, Masella B, Guarini A, Fatica A, Peschle C, Bozzoni I. 2007 The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation. PNAS, 104:19849-19854.

9. Fatica A, Rosa A, Fazi F, Ballarino M, Morlando M, De Angelis FG, Caffarelli E, Nervi C, Bozzoni I. 2006. MicroRNAs and hematopoietic differentiation. Cold Spring Harb Symp Quant Biol. 71:205-10.

10. Oeffinger M, Fatica A, Rout MP, Tollervey D. 2007. Yeast Rrp14p is required for ribosomal subunit synthesis and for correct positioning of the mitotic spindle during mitosis. Nucleic Acids Res. 35:1354-66.

11. Nervi C, Fazi F, Rosa A, Fatica A, Bozzoni I. 2007. Emerging role for microRNAs in acute promyelocytic leukemia. Curr Top Microbiol Immunol. 313:73-84

12. Houalla R, Devaux F, Fatica A, Kufel J, Barrass D, Torchet C, Tollervey D. 2006. Microarray detection of novel nuclear RNA substrates for the exosome.Yeast 23: 439-454.

13.  Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C, Bozzoni I. 2005. A mini-circuitry comprising microRNA-223 and transcription factors NFI-A and C/EBPa regulates human granulopoiesis. Cell 123: 819-831.

14. Ballarino M, Morlando M, Pagano F, Fatica A, Bozzoni I. 2005. The cotranscriptional assembly of snoRNPs controls the biosynthesis of H/ACA snoRNAs in Saccharomyces cerevisiae. Mol Cell Biol 25: 5396-5403.

15. De Marchis M L, Giorgi A, Schinina ME, Bozzoni I, Fatica A. 2005. Rrp15p, a novel component of pre-ribosomal particles required for 60S ribosome subunit maturation. RNA 11: 495-502.

 

Last Updated on Friday, 24 January 2014 14:11  
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