Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy

Bertero A, Fields PA, Smith AST, Leonard A, Beussman K, Sniadecki NJ, Kim D, Tse H, Pabon L, Shendure J, Noble WS, Murry CE

Journal of Cell Biology, 2019



Chromatin organization is regulated by the nuclear lamina and plays a critical role in development and disease progression in cardiomyocytes. For example, cardiac laminopathy, which involves changes to the electrophysical properties of cardiomyocytes, is associated with mutations in A-type nuclear lamins. In this study, the authors were interested in understanding the functional changes that occur during chromatin organization in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with a haploinsufficent mutation for lamin A/C. A robust in vitro model was established using mutant and wild-type hiPSC lines to study the progression of cardiac laminopathy in differentiating cardiomyocytes. A multiwell microelectrode array (MEA) system was used to demonstrate the unusual electrophysiology of mutant hiPSC-CMs, such as irregular and reduced beat rates, elevated field potential (FP) amplitudes, and prolonged field potential durations (FPDs) when compared to their wild-type counterparts. However, while lamin A/C deficient hiPSC-CMs did exhibit changes in their electrophysiology and chromatin organization, our understanding of pathogenesis of cardiac laminopathy is still limited. Thus, future studies will need to focus on expanding the number of hiPSC lines with mutations that cause more global changes to chromatin topology.