Davide Gabellini
Davide Gabellini
affiliation: San Raffaele Scientific Institute
research area(s): Molecular Biology, Stem Cells And Regenerative Medicine
Course: Cell and Molecular Biology
University/Istitution: Università Vita-Salute San Raffaele
2008- Senior HSR Researcher Division of Regenerative Medicine, Fondazione Centro San Raffaele del Monte Tabor, Milano, Italy
2006- DTI Scientist Stem Cell Research Institute, DIBIT, H. San Raffaele, Milano, Italy
2000-2006 Postdoc HHMI, Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, USA
1996-2000 PhD, Institute of Molecular Genetics, CNR of Pavia, Italy.
Although most cells contain an identical set of genes, they can be extremely diverse in appearance and function. It is the selective expression and repression of genes that determines the specific properties of individual cells. Maintenance of the correct gene expression pattern is fundamental for organism integrity. For this reason, failure to repress genes appropriately has been connected to many human diseases. An important example of a genetic disorder associated to transcriptional imbalance is facioscapulohumeral muscular dystrophy (FSHD). FSHD is one of the most common hereditary diseases of muscle. Unlike the majority of genetic diseases, FSHD is not due to a classical mutation within a protein-coding gene. Our results suggest that FSHD is due to an epigenetic alteration causing over-expression of the gene FRG1. Accordingly, transgenic mice over-expressing FRG1 develop an FSHD phenotype and represent the first animal model of the disease. Our group is interested in elucidating the role of the epigenome in shaping the skeletal muscle and in the pathogenesis of muscular dystrophy. We are using cellular and animal models of FSHD to elucidate the pathways altered in the disease and to develop and test possible therapeutic approaches.
1. 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. Molecular Therapy in press
2. Cabianca DS, Gabellini D 2010 FSHD: Copy Number Variations on the theme of Muscular Dystrophy. Journal of Cell Biology 191:1049-60
3. Pistoni M, Ghigna C, Gabellini D 2010 Alternative Splicing and Muscular Dystrophy RNA Biology 7:441-52
4. Neguembor MV, Gabellini D 2010 In Junk We Trust: repetitive DNA, epigenetics and facioscapulohumeral muscular dystrophy. Epigenomics 2:271-287
5. Gabellini D, D"Antona G, Moggio M, Prelle A, Zecca C, Adami R, Angeletti B, Ciscato P, Pellegrino MA, Bottinelli R, Green MR, Tupler R 2006 Facioscapulohumeral Muscular Dystrophy in Transgenic Mice by Over-Expression of FRG1 Nature 439:973-977
6. Tupler R, Gabellini D 2004 Molecular basis of facioscapulohumeral muscular dystrophy Cell Mol Life Sci 61:557-566
7. Tupler R, Gabellini, D. 2004. FSHD: A disorder of muscle gene derepression. In: Upadhyaya M, Cooper, DN, editor. Facioscapulohumeral Muscular Dystrophy (FSHD). Abingdon Oxfordshire OX14 4RN: Taylor & Francis. p 250.
8. Gabellini D, Green MR, Tupler R 2004 When enough is enough: genetic diseases associated with transcriptional derepression Curr Opin Genet Dev 14:301-307
9. Gabellini D, Colaluca IN, Biamonti G, Giacca M, Orioli D, Falaschi A, Riva S, Peverali F 2003 Proteolysis of HOXC10 by Anaphase-Promoting Complex/Cyclosome Plays a Role in Mitotic Progression EMBO J 22:3715-3724
10. Gabellini D, Tupler R, Green MR. 2003 Transcriptional derepression as a cause of genetic diseases Curr Opin Genet Dev 13:239-245
11. Gabellini D, Green MR, Tupler R 2002 Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle Cell 110:339-348
Project Title:
Role of alternative splicing in the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD).
One of the most remarkable observations stemming from genome sequencing of diverse species is that the number of protein-coding genes in an organism does not correlate with its complexity.
Alternative splicing (AS) is the process by which exons of primary transcripts are spliced in different arrangements to generate distinct isoforms. Consequently, AS greatly expand the information content of genomes and plays a major role in the generation of the functional complexity in higher eukaryotes. Hence, understanding the mechanisms that regulate AS is essential for a functional interpretation of genomic sequences. An additional incentive to the comprehension of AS is that as many as 50% of human genetic diseases due to point mutations are caused by aberrant AS.
FSHD is one of the most important muscular dystrophies but its molecular pathogenesis remains largely unknown. Over-expression of FSHD region gene 1 (FRG1) in mice, frogs and worms causes an FSHD-like phenotype. Since previous studies have suggested a role for FRG1 in AS, we used AS microarrays to conduct a genome-wide analysis in FRG1 mice. We found that AS changes parallel the differential susceptibility of individual muscles to the FRG1 over-expression and the progression of the disease over time. Notably, several controls strongly suggest that the AS changes identified are directly due to FRG1 over-expression. Importantly, a number of the aberrant AS events identified belong to genes mutated in muscular dystrophy.
The PhD student will characterize the molecular mechanism through which FRG1 regulates AS by studying the interaction of FRG1 with RNA targets and splicing factors. Moreover, the student will define the biological role in muscular dystrophy of the aberrantly expressed AS isoforms by over-expression and knockdown studies in muscle cells.

This project will help designing therapeutic strategies targeting the pathogenic effect of FRG1 up-regulation. Besides the obvious translational ramifications, results from this research will significantly contribute to our understanding of post-transcriptional regulation in higher eukaryotes.

Project Title:
Role of FRG1 in the extra-muscular manisfestation of facioscapulohumeral muscular dystrophy (FSHD).
FSHD is one of the most important muscular dystrophies but its molecular pathogenesis remains largely unknown. Over-expression of FRG1 has been proposed as a possible cause of the disease. Accordingly, muscle-specific transgenic mice over-expressing FRG1 develop a muscular dystrophy resembling FSHD.
A number of extra-muscular manifestations have been described in FSHD including sensorineural hearing loss, retinal telangiectasias, mental retardation, and cardiac defects. To investigate whether over-expression of FRG1 is also responsible for the extra-muscular symptoms of FSHD patients, we have generated transgenic mice over-expressing FRG1 ubiquitously (CAG-FRG1).
Aim of the PhD project is the characterization of this novel model of FSHD. The initial analysis of will be focused mainly on three organs: brain, eye and heart.

A. Evaluation of mental retardation.
FSHD has been associated to central nervous system (CNS) disorders, including sensorineural hearing loss, schizophrenia, epilepsy and mental retardation. MRI studies found a significant reduction in gray matter volumes and higher cerebrospinal fluid volumes in FSHD patients. To analyze CNS defects in CAG-FRG1 mice we will perform MRI analysis and behavioral tests.

B. Evaluation of ocular defects.
Peripheral retinal capillary abnormalities, comprising telangiectasis, closure, leakage and microaneurysm formation are an integral part of FSHD. Interestingly, a role of FRG1 in angiogenesis has recently been reported. To analyze retinal defects in CAG-FRG1 mice we will perform retinal angiography and retinal histology studies.

C. Evaluation of cardiac defects.
On a preliminary anatomo-pathological evaluation, CAG-FRG1 mice show morphological defects in the heart. Further analysis of cardiac defects in CAG-FRG1 mice will involve echocardiography and cardiac histomorphological analysis.

These studies will define the molecular events leading to FSHD and will lay the basis of effective treatments for FSHD.