The fundamental mechanisms governing how cells form an identity such as becoming a muscle cell or a nerve cell are not fully understood. Multiple diseases, including cancer, have been linked to cells going down the wrong developmental path during maturation. A new study from the Perelman School of Medicine at the University of Pennsylvania suggests that the ability of a stem cell to differentiate into cardiac muscle (and by extension other cell types) depends on what portions of the genome are available for activation, which is controlled by the location of DNA in a cell’s nucleus.
“The implications of this study are far-reaching,” Epstein said. “The ability to control how quickly a cell differentiates to make cardiac tissue or other cell types has important implications for regenerative medicine.” In addition, in many diseases, including cancer, cells express genes that they normally would not, which changes their identity.
The study also addresses a classic concept in stem cell and developmental biology called “competence” — the ability of a cell to respond to its environment in specific ways. For example, some lung cells respond to cigarette smoke to become cancerous, while others do not. The investigators surmise that this difference could be due to the availability of regions of the genome to respond to chemicals associated with cigarette smoke, or because the unavailability of those same genes in non-responding cells are locked away in silenced domains at the nuclear periphery.
Jain, Epstein, and others are working to determine if changes in genome domains at the nuclear periphery, or the molecular tethers that keep them there, are responsible for cancer susceptibility. This approach could also be applied to other diseases, such as several forms of muscular dystrophy, heart failure, and premature aging due to inherited, genetic abnormalities of the lamina. “We aim to determine if these mutations lead to abnormal tethering of DNA and changes in gene expression and disease.”
In the future, the researchers plan to manipulate the spatial organization of DNA to coax cells to adopt a different identity and ask what role that may play in human diseases linked to a loss of cellular identity, including diabetes, Alzheimer’s disease, forms of heart failure, and cancer. The group is also expanding their work to study patients with mutations in components of their nuclear lamina.