SCIE.03.2 - Dissecting the contribution of nuclear mechanics for the treatment of Kabuki Syndrome

The role and importance of phase transition in modulating multiple aspects of cell biology is widely acknowledged, yet we still lack molecular insights about the mechanism governing the assembly and modulation of biomolecular condensates. Recent findings suggest that the mesoscale organization of chromatin within biomolecular condensates modulates both the genetic and nongenetic function of the genome. We recently contributed on this topic by investigating the interplay between chromatin-associated condensates and nuclear mechanical properties and its relevance in the pathogenesis of Kabuki Syndrome (KS). This genetic disease is characterized by postnatal growth delay, craniofacial dysmorphism, immunological defects and mild mental retardation. Haploinsufficiency of KMT2D, which codify for the chromatin regulators MLL4 has been identified as the major underlying cause of KS. We have shown that MLL4 plays a major role in determining the chromatin organization and the nuclear mechanical properties. We postulate that the biophysical properties of chromatin-associated condensates determine the nuclear structure and its mechanics, thereby tuning the cellular mechano-response. In this respect, we are investigating the role of RNA in modulating the assembly of MLL4-centered condensates and their impact on chromatin organization and mechanotransduction. In addition, we determined the contribution of external mechanical forces to determine the chromatin organization and the dynamic assembly of biomolecular condensates. During the Congress, we will illustrate the dynamic relationship between the nuclear architecture and the cell mechanotransduction, which determine the capability of progenitors to properly differentiate during development and tissue homeostasis. Finally, we will discuss the role of the nuclear architecture in determinizing the clinical features associated with Kabuki Syndrome and how targeting the mechano-sensor ATR can ameliorate the associated abnormalities.