MOLECULAR DISSECTION OF TWO HUMAN CHROMATIN DISEASES, RETT SYNDROME AND ICF SYNDROME

Failure of correct gene expression underlies many human genetic disorders. In monogenic disorders, altered expression of a single gene can result from loss of the gene and/or modification of regulative control of gene expression. A class of monogenic disorders presents mutations of factors which mediate gene regulation, that can regulate more target genes. They also alter gene expression and so tend to result in syndromes in which several biological systems are disturbed. The modification of DNA, organized in chromatin, such as methylation, is integral to the correct control of gene expression in mammals. It is now possible to identify a new class of human diseases, the “Chromatin Diseases”, that result from mutations in the components of chromatin or in the enzymes that modify chromatin structure. We are interested in two human pathologies, ICF syndrome and Rett syndrome, which describe two different steps of the chromatin based control of gene expression: the effect of the alteration of the methylation level, caused by mutations in DNA methyltransferase 3B in ICF syndrome, and the effect of failure in the interpretation of the methylation signal, caused by mutations in the generalized repressor of gene expression MECP2 in Rett syndrome. While the ICF syndrome (immunodeficiency, centromeric instability and facial anomalies) is quite rare, the Rett syndrome represents the second cause of mental retardation in live born females. Even the genetic defect is known for both these syndromes, it is now crucial to understand the molecular mechanisms altered in these syndromes and the affected target genes. The aim of this project is to molecularly characterize the target genes directly regulated by MECP2 or DNMT3B genes and the modifications of chromatin in the regulation of these genes. A better knowledge of these diseases will inform either about chromatin-based mechanisms of gene expression themselves and about ways in which the disease phenotypes might be ameliorated.