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October 13, 2017

Genomic Wallflowers Join in Cell Identity Dance

A layer of gene regulation depends on genome–nuclear lamina interactions that may be sensitive to lineage cues, with implications for stem cell fate. These interactions involve Hdac3, which may act as a tether coordinating the organization of chromatin. (Left) In the nucleus, cell fate is determined by which gene programs are available and which are tucked away. (Right) The location of the Titin gene (red) in a cardiac myocyte. The nuclear lamina is shown in green and troponin fibers in yellow. Chromatin containing key genes required for particular cell fates are sequestered at the nuclear periphery. Genomic regions containing cardiac genes are released from the periphery upon differentiation of stem cells into cardiac myocytes. [Kate Isenberg]

  • Keeping to the margins of the nucleus, many genes seem to be left out of the cell development dance. These genes, like wallflowers at the prom, might even appear to be physically tethered. In fact, according to a new study, they are physically tethered—but not always. There are times when the tethers are released and seemingly shy genes are drawn into the whirl of activity that drives cell differentiation. These genes may even alter the choreography within stem cells that determines whether they become a muscle cell, say, or a nerve cell.

    The tether is an epigenetic enzyme called histone deacetylase (Hdac3). It organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. In other words, it attaches DNA to the nuclear periphery.

    This connection—not just the physical connection, but also the connection to lineage restriction—was uncovered by scientists based at the Perelman School of Medicine at the University of Pennsylvania. These scientists have published a study suggesting that 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.

    Details appeared October 12 in the journal Cell, in an article entitled “Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction.” This article explores how progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. Lineage-specific genes, it turns out, may be consigned to the nuclear lamina, depending on how peripheral heterochromatin is organized. And these genes may come into play, influencing cellular differentiation, if the chromatin is reorganized.

    "The basis of this study is understanding the ability of a cell to respond to molecular cues to correctly become one cell type or another," said senior author Rajan Jain, M.D., an assistant professor of cardiovascular medicine. "We wanted to know how that is achieved, step by step, because stem cells, capable of becoming any cell type in the body, give rise to cardiac muscle cells."

    Dr. Jain and co-senior author Jonathan A. Epstein, M.D., the executive vice dean and chief scientific officer at Penn Medicine, pointed out that their study sheds light on the fundamental mechanisms governing how cells form an identity, such as becoming a muscle cell or a nerve cell. These mechanisms could help explain how multiple diseases, including cancer, may occur if cells go down the wrong developmental path during maturation.

    Also, the study suggests that knowing how to control how quickly a cell differentiates as it matures has important implications for regenerative medicine.

    “Deletion of Hdac3 in cardiac progenitor cells releases genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes,” wrote the article’s authors. “In contrast, restricting Hdac3 to the nuclear periphery rescues myogenesis in progenitors otherwise lacking Hdac3.”

    Essentially, the scientists removed Hdac3 in stem cells during heart cell differentiation. The scientists observed that when they untethered regions of DNA containing heart-specific genes, those genes became activated, leading to precocious, overly fast differentiation.

    "The implications of this study are far-reaching," Dr. 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.

    More generally, the study suggests that availability of genomic regions for activation by lineage-specific factors is regulated in part through dynamic chromatin–nuclear lamina interactions. Some regions of the genome are unavailable to be expressed because they are packaged tightly against the inner membrane of the cell nucleus (the lamina). These sequestered and silenced regions of DNA are called lamina-associated domains, or LADs. The Cell study suggests that the specific regions of silenced DNA at the periphery help define a cell's identity.

    For example, if nerve cell genes are held silent as LADs, they cannot be expressed, so the cell does not become a neuron. However, if heart cell genes are released and available to be expressed, as happens during heart development, then those cells become cardiac muscle. Cell biologists have known for many years that some DNA is found near the inner nuclear membrane, but the function of this localization has been unclear.

    "Our work suggests that a cell defines its identity by storing away in an inaccessible closet the critical genes and programs necessary for it to mature into another cell type," noted Dr. Jain. "In other words, a cell is 'who' it is because it has silenced 'who' it isn't."

    Finally, the study also addressed 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 nonresponding cells are locked away in silenced domains at the nuclear periphery.

    Dr. Jain, Dr. 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.

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