Dissecting the contribution of altered nuclear mechanotransduction to the pathogenesis of Kabuki Syndrome and its therapeutic implications

Kabuki Syndrome (KS) is a rare genetic disease characterized by postnatal growth delay, craniofacial dysmorphism, immunological defects and mild mental retardation. Although the underlined genetic cause of KS has been identified, it still unclear the mechanism by which the MLL4 loss-of-function (LoF) causes the development and the progression of the disease. MLL4 is a protein involved in regulating the functionality of the chromatin, which is organized in compartments to modulate the gene function and genome stability. We recently discovered that the same protein is also involved in determining the “nongenetic function of the genome”, namely regulating the physical properties of the chromatin, which influence the cellular response to mechanical stimuli. In this project we aim to determine the mechanism of action of MLL4, to determine the contribution of specific mutations to the alternated response to mechanical stimuli, in the attempt to define a novel therapeutic approach that could alleviate some of the clinical manifestations associated with KS.