DC8: Biobanking, DNA-methylation signature and 3D genome organization in the study of Kabuki syndrome-UNINA

DC8 (UNINA) will dissect the impact of pathogenic variants in KMT2D by combining Kabuki syndrome disease modelling with omics technologies and computational approaches. Specifically, DC8 will investigate the epigenetic and transcriptomic profiles and 3D genome organization using KS hiPSC-derived differentiated cells and organoids (e.g. brain and heart).

         To reach these goals, DC8 will expand the existing biobank of CPs, mainly by increasing the KS patients’ cohort as well as controls. After a training period, the DC8 will adopt quantitative array-based methylation measurement at the single-CpG-site level, offering high resolution for understanding DNA epigenetic changes of all the KS models generated.

         Then, DC8 will adopt the most recent technologies at single cell level resolution to unveil the overall alterations affecting chromatin structure and function as consequences of KMT2D pathogenic variants. Specifically, single cell Multiome ATAC + scRNASeq will simultaneously provide profile gene expression and open chromatin state from the same cell, while single cell Hi-C technologies will define the 3D chromatin interaction landscape.         Overall, this project will provide insights into how changes in chromatin accessibility, 3D spatial organizations and associated epigenetics profiles will lead to the defects that are clinically relevant in Kabuki syndrome.