 A long helix. That's what you may picture when thinking of DNA, the material that makes up our genome. But in reality, it's more like a big bowl of spaghetti, with chromosomes stretched out and tangled together. Scientists are coming to realize that the strands are not arranged randomly, but instead are actually organized in important ways and can even help determine if a cell becomes a muscle or a brain cell. Researchers in the laboratory of Rajan Jain and Kiran Musimiro at the University of Pennsylvania have been exploring this intriguing connection between the 3D organization of the genome and the identity of a cell. They and other groups have seen that certain areas of the genome form contacts with the nuclear lamina, a structure at the outer edge of the nucleus. These contacts seem to prevent the expression of the gene that is touching the lamina. The scientists wanted to figure out whether the contacts between the DNA and the lamina are different across different types of cells, and whether these contacts contribute to identity. Their findings have been published in the journal Cell Stem Cell in an article titled Pathogenic Laminae Variants Disrupt Cardiac Lamina Chromatin Interactions and DeRepress Alternative Fate Genes. In efforts led by Parisha Shah and Jane Lu, the research team used human-induced stem cells and drove them to turn into three different types. Heart cells are cardiomyocytes, liver cells, hepatocytes, and fat cells adipocytes. When they mapped which regions of DNA were in contact with the nuclear lamina, they saw that it was different across the three cell types. Genes associated with unwanted fates were organized at the lamina, suggesting that the spatial organization of the genome may have a role in the identity of the cell. What might happen if the normal DNA lamina contacts were disrupted? Would cells then lose their identity? To address this, the scientists disrupted the nuclear lamina by making mutations or changes in a gene that is important for the structure of the nuclear lamina. The particular mutations they chose occur in people who have a certain type of cardiomyopathy or heart disease. The mutations disrupted several features of the heart cells. First, they impaired their function, similar to what is seen in patients. Next, the group found that mutations disrupted the contacts between the genome and the nuclear lamina in a very specific, almost predictable way. And the cardiomyocytes started to express nerve cell genes. By contrast, the liver and fat cells were largely unaffected by the mutations, both in terms of function and when looking at the genome lamina interactions. These findings show that the interactions between the genome and the lamina can be specific and are very important for maintaining a cell's identity, since disrupting those domains in heart cells leads to altered gene expression and cell function. The team was also able to model a human disease called laminate cardiomyopathy with their system. People with the particular mutations that were studied have dysfunctional hearts and often need transplants. Continued work with these cells can increase our understanding of how the genomic architecture shapes cell fate and how the mutations lead to this disease, which can then inform the development of new and better treatments. And last but not least, this research may also aid in our quest towards precision medicine by helping predict which patients with mutations will end up having heart failure and getting these patients treated as early as possible.