Genetics and cell biology
Gene expression and muscular dystrophy
Only about 1% of our genome encodes for the ~20000 human proteins, which are similar in number and largely orthologous to those found in organisms of significant lower complexity. Interestingly, up to two thirds of our genome is composed of repetitive sequences that are dynamically transcribed in different cells and developmental stages producing a vast pool of ncRNAs. Thus, ncRNAs produced by DNA repeats may hold the key to understanding the regulatory complexity inherent in advanced biological networks. Nevertheless, their biological relevance and mechanism of action remain poorly explored.
The unit main interest is to understand how gene expression instructs the complex programs typical of higher eukaryotes. We are particularly interested in the regulation of muscle- and B-cell differentiation, and the associated diseases using FSHD muscular dystrophy and acute lymphoblastic leukemia, respectively, as paradigms. FSHD is the most prevalent neuromuscular disease affecting males and females of all ages. The disease is caused by chromatin relaxation leading to inappropriate gain of expression of the double homeobox transcription factor DUX4, which is highly toxic to skeletal muscle leading to disease. B cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer and the major cause of cancer-related death among children and young adults. DUX4 translocations have been reported in up to 7% of B-ALL patients and define a new B-ALL subtype, characterized by deregulation of the ETS transcription factor gene ERG, and widespread hypomethylation compared to normal B cells or other ALL subtypes. DUX4 rearrangements in B-ALL mostly involve insertion of a C-terminally truncated DUX4 sequence retaining the DNA binding domain of WT DUX4 in the immunoglobulin heavy chain (IGH) locus leading the production of the oncogenic DUX4-IGH fusion protein under the control of the IGH enhancer. We combine biochemistry, cell biology and molecular biology tools together with genome wide approaches in order to understand the mechanisms controlling DUX4 and DUX4-IGH expression and activity. We evaluate the therapeutic relevance of our findings using cellular and animal models of the diseases.
Pedrotti S, Caccia R, Neguembor MV, Garcia-Manteiga JM, Ferri G, de Palma C, Canu T, Giovarelli M, Marra P, Fiocchi A, Molineris I, Raso M, Sanvito F, Doglioni C, Esposito A, Clementi E, Gabellini D. The Suv420h histone methyltransferases regulate PPAR-γ and energy expenditure in response to environmental stimuli. Science Adv. 2019 Apr 17;5(4):eaav1472.
Castiglioni I, Caccia R, Garcia-Manteiga JM, Ferri G, Caretti G, Molineris I, Nishioka K, Gabellini D. The Trithorax protein Ash1L promotes myoblast fusion by activating Cdon expression. Nature Commun. 2018 Nov 28;9(1):5026.
Casa V, Runfola V, Micheloni S, Aziz A, Dilworth FJ, Gabellini D. Polycomb repressive complex 1 provides a molecular explanation for repeat copy number dependency in FSHD muscular dystrophy. Hum Mol Genet. 2017 Feb 15;26(4):753-767.
Caron L, Kher D, Lee KL, McKernan R, Dumevska B, Hidalgo A, Li J, Yang H, Main H, Ferri G, Petek LM, Poellinger L, Miller DG, Gabellini D, Schmidt U. A Human Pluripotent Stem Cell Model of Facioscapulohumeral Muscular Dystrophy-Affected Skeletal Muscles. Stem Cells Transl Med. 2016 Sep;5(9):1145-61.
Ferri G, Huichalaf CH, Caccia R, Gabellini D. Direct interplay between two candidate genes in FSHD muscular dystrophy. Hum Mol Genet. 2015 Mar 1;24(5):1256-66.
Runfola V, Sebastian S, Dilworth FJ, Gabellini D. Rbfox proteins regulate tissue-specific alternative splicing of Mef2D required for muscle differentiation. J Cell Sci. 2015 Feb 15;128(4):631-7.
Huichalaf C, Micheloni S, Ferri G, Caccia R, Gabellini D. DNA methylation analysis of the macrosatellite repeat associated with FSHD muscular dystrophy at single nucleotide level. PLoS One. 2014 Dec 29;9(12):e115278.
Neguembor MV, Xynos A, Onorati MC, Caccia R, Bortolanza S, Godio C, Pistoni M, Corona DF, Schotta G, Gabellini D. FSHD muscular dystrophy region gene 1 binds Suv4-20h1 histone methyltransferase and impairs myogenesis. J Mol Cell Biol. 2013 Oct;5(5):294-307.
Xynos A, Neguembor MV, Caccia R, Licastro D, Nonis A, Di Serio C, Stupka E, Gabellini D. Overexpression of facioscapulohumeral muscular dystrophy region gene 1 causes primary defects in myogenic stem cells. J Cell Sci. 2013 May 15;126(Pt 10):2236-45.
Pistoni M, Shiue L, Cline MS, Bortolanza S, Neguembor MV, Xynos A, Ares M Jr, Gabellini D. Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD). PLoS Genet. 2013;9(1):e1003186.
Cabianca DS, Casa V, Bodega B, Xynos A, Ginelli E, Tanaka Y, Gabellini D. A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy. Cell. 2012 May 11;149(4):819-31.
Bortolanza S, Nonis A, Sanvito F, Maciotta S, Sitia G, Wei J, Torrente Y, Di Serio C, Chamberlain JR, Gabellini D. AAV6-mediated systemic shRNA delivery reverses disease in a mouse model of facioscapulohumeral muscular dystrophy. Mol Ther. 2011 Nov;19(11):2055-64.