 The human body is made up of 200 different types of cells which make up to the more than 30 trillion cells in our bodies. This number is even more amazing when you consider that all of these cells arise from a single celled embryo. So how are such spectacular multitudes of cells formed in the human body? Let's explore a little further. In order for such a wide variety of cells to form, each cell has to establish and maintain its identity. A heart cell needs to decide that it's going to be a heart cell, and then commit. A heart cell should not spontaneously turn into a liver cell. Cells gain their identity by turning particular genes on and off depending on the cell's function. For example, skin cells will turn on genes that allow for hair growth, whereas kidney cells would turn these off. These patterns of gene activity define cellular identity, but we don't fully understand how so many genes are controlled and maintained in such a coordinated way. Scientists believe one way genes are controlled is by how the DNA organizes itself in the nucleus. The nucleus contains most of the genetic material needed by a cell, but not every cell needs access to all the genes. Some recent data suggests that how DNA is packaged in three dimensions in the nucleus might affect how and when genes are turned on or off. It has been known for many years that genes contained in DNA held close to the periphery of the nucleus are not turned on and instead kept silent. Some proteins can help to tether DNA to the nuclear periphery, but how this might affect the function or development of the cell has been unknown. A research team led by physician scientists Rajan Jain and Jonathan Epstein at the Pearlman School of Medicine at the University of Pennsylvania set out to explore if and how DNA organization in the nucleus influences the ability of cells to establish an identity in response to specific signals. Their findings are published in the journal Cell in an article titled Genome Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction. The group started their study by asking what would happen to heart cell development if they removed a specific nuclear factor HDAC3. They chose to study HDAC3 for several reasons. First, HDAC3 has a known role in heart development. Second, HDAC3 is known to control whether genes are on or off. And finally, HDAC3 has been shown to be localized to the nuclear periphery. The authors were determined to see if there was a link between all of these phenomena that might have something to do with how DNA is organized in the nucleus and cellular identity. To test this, the group started by deleting HDAC3 from stem cells, cells that have the potential to become any type of cell. They found that removing HDAC3 made the stem cells biased towards making heart myocytes, special muscle-like cells that allow the heart to pump. This means that in normal conditions, when HDAC3 is present, it prevents heart cell development. But how? By both visualization and DNA sequencing, the researchers found that in these stem cells, heart-specific genes were localized at the nuclear periphery, where they are kept silent. It turns out that HDAC3 tethers heart genes to the periphery by linking the genes to the nuclear lamina. When HDAC3 is absent in stem cells, some heart genes erroneously moved to the center of the nucleus, as they would in cells destined to become heart cells. Therefore, in stem cells without HDAC3, the pattern of gene organization is akin to heart cells, which shows that HDAC3 normally represses the heart cell fate by repressing the expression of heart genes in stem cells, until the correct environmental signals are present. This study reveals HDAC3's role as a tether, which is particularly interesting because this role is independent of HDAC3's well-defined role in regulating a gene's on-off state. This research also defines both a previously unknown function for HDAC3 in heart development, as well as a mechanism for how cellular identity is achieved in the heart by changing the three-dimensional organization of the DNA in the nucleus. This work also begins to address fundamental questions in developmental biology. How do cells form their identity? Why can some cells respond to certain environmental signals while others cannot? Answers to these questions can lead to many important advances for human health. For instance, there is a large group of diseases known as laminopathies that are caused by defects in the nuclear lamina. Understanding what role the nuclear lamina plays in gene regulation can put researchers on the path towards better treatment for these diseases. Additionally, there are many other types of diseases that occur because of a loss of cellular identity, such as diabetes, Alzheimer's, and cancer, that can also benefit from insight into how cells establish identity. The group is excited to undertake many studies exploring how the nucleus is organized, how this organization is achieved, and how this organization impacts cell identity.