PROJECT Overview

Rationale

Chromatin disease are genetic diseases resulting from mutations in components of chromatin and/or in enzymes that modify DNA methylation and histone modifications.
This alters chromatin status at specific genes and/or genomic regions, thereby causing drastic effects on gene expression.

A main concept is that Chromatin Diseases are an ideal model system since their nature as monogenic diseases makes them more “molecularly amenable” with respect to other multifactorial diseases such as cancer.
Another main concept is that epigenetic factors (contrary to genetic factors) are potentially reversible and “druggable” and consequently constitute potential drug targets for the treatment of human diseases,including cancer, thus making the investigation of epigenetic factors involved in chromatin remodelling a priority for research.

Following the above-mentioned concepts, the specific objectives of DISCHROM project are:

1) to define the DNA methylation machinery involved in regulating the process
    of differentiation in stem cells
2) to define the effects of DNA methylation and chromatin machinery in somatic cells
    in specific CDs, such as immunodeficiency–centromeric instability–facial anomalies (ICF)
    syndrome and facioscapulohumeral muscular dystrophy (FSHD)
3) to define the molecular mechanisms that regulate MeCP2 and ATRX functions, such as:
    a) the role of MECP2 in shaping genomic architecture
    b) the functional significance of CDKL5-mediated MeCP2 phosphorylation
    c) the contributions of micro RNAs as downstream targets for MeCP2
    d) the interaction of ATRX with target genes and the effect of ATRX knock-down
        or dislocalization from heterochromatin
4) to in-vivo screen for new pharmacological treatments of a paradigmatic CD, Rett syndrome
5) to develop technologies for deciphering the global molecular basis of CDs,
    leading to novel therapeutic approaches.

Project organization

The main scientific objective of the program will be addressed by the research activities
the description of which is broken down to 5 Work Packages namely:

1. Role of DNA methylation in the control of gene silencing during development
2. Analysis of DNA methylation and chromatin machineries affected in somatic cells
    of human disorders, ICF and FSHD
3. The role of the chromatin proteins MeCP2 and ATRX in health and diseases
4. Treating chromatin diseases: the case of Rett syndrome
5. Chromatin Diseases Oriented Techology

Consortium

In addressing these aims the DisChrom ITN has assembled 12 groups of European scientists with cross-disciplinary expertise and capabilities.
The group includes individuals with clinical expertise in defining CDs as well as scientists who are focused on dissecting the mechanisms that are perturbed in the four CDs studied here.