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Chromatin diseases: from basic mechanisms to therapy

Final Report Summary - DISCHROM (Chromatin diseases: from basic mechanisms to therapy)

The scope of “DisChrom” ITN is to promote research and training in the field of chromatin diseases. Chromatin diseases are genetic pathologies resulting from mutations in structural components of chromatin or in enzymes that biochemically modify chromatin, altering chromatin status and causing drastic effects on gene expression. Their frequency ranges from very rare (i.e.: ICF syndrome, roughly <100 patients worldwide) to quite common pathologies (i.e.: Rett Syndrome, 1/10.000 born females). Our interest is focused on four chromatin diseases: i) Rett syndrome; ii) Alpha thalassemia with mental retardation (ATRX) syndrome;iii) Facioscapulohumeral muscular dystrophy (FSHD); iv) Immunodeficiency, Centromeric region instability, Facial anomalies (ICF) syndrome.
Molecular studies on these pathologies thus have a twofold value: to shed light on the intricate interplays between different levels of control of gene expression acting in the mammalian nucleus and to pave the way toward new and more effective strategies to approach the treatment of this expanding class of diseases. A novel generation of scientists, with expertises ranging from molecular biology, to medical genetics to next generation technologies and bioinformatics is needed, to cover all aspects of the field. This is the aim and the challenge of many European efforts, of which the DISCHROM Multi-ITN Consortium is a representative
To address the proposed aims the DisChrom ITN assembled a group of scientists with cross-disciplinary expertise and capabilities. The group includes individuals with clinical expertise in defining chromatin diseases as well as scientists who are focused on dissecting the mechanisms that are perturbed in the four pathologies of interest. Two technology-related teams developed and provided updated technologies. They were also heavily involved in the training of DisChrom students via the organization of workshops, lecture courses, specific visits and secondments. DisChrom Network thus provided a framework for the very high-level training of young researchers, that received strong backgrounds in molecular, cellular and developmental biology, genomics, bioinformatics, chromatin biology and epigenetics. Furthermore, our students developed expertise in many cutting edge methodologies and tools, such as imaging and high throughput gene technologies. As a result, DisChrom students will be highly competitive in performing independent research in various areas of biology and will represent a new breed of scientists trained in contemporary post-genomic biology using advanced technological tools to tackle human disease.
Since the starting of the project, our work pursued the scientific issues proposed in Final Annex and its five workpackages. As a key issue, we aimed to unravel the role of DNA methylation, one of the main epigenetic mechanisms controlling gene expression, of its machinery and function during development and how these may be affected in specific diseases.
Besides these scientific contributions, a very important point is that so far for the vast majority of chromatin diseases no treatment is as yet available. As a model pathology, we proposed new ways for treatment of Rett syndrome. In this light, we improved and developed new “in vivo protocols” in order to evaluate several key aspects of the RTT phenotype. At the same time, we are developing new drug treatments to improve such deficits, with encouraging partial, but significant, improvement of the disease.
In addition, often, the pathogies here studied represent a social problem, since that, contrary to common diseases, rare diseases are often not interesting to big pharma for developing therapeutic interventions. In addition, due to the syndromic nature of these diseases, patients often require the help of teams of physicians: this is a burden of National Health Systems, that can be alleviated if, through a focused research, new and more effective treatments may be addressed to these patients.