Nongenetic functions of the genome

The nongenetic roles of the nucleus The eukaryotic cell nucleus provides a home for the genetic material and accessory proteins. As a physical entity, the nucleus also plays an important role in cell dynamics. Bustin and Misteli Review the impacts that the nucleus can have as a nongenetic force. For example, compacted DNA and the nuclear membrane affect nuclear morphology, the cellular response to mechanical force, cell migration, and cell signaling. Chromatin is not only affected by physical forces in cells but participates in a crosstalk of signaling inside cells. Science, this issue p. 10.1126/science.aad6933 BACKGROUND The genome is the carrier of the hereditary information that defines an organism. Most genomes consist of a linear polymer of DNA wrapped around octameric histone protein complexes to generate a chromatin structure resembling beads on a string, which further folds and organizes into domains of various sizes and degrees of compaction that are functionally relevant to the regulation of all genomic activities. A myriad of proteins, including remodeling complexes and transcription factors, bind to chromatin in a combinatorial fashion to coordinate gene expression programs. The well-accepted major functions of the genome are to store and propagate the genetic material and to control the expression of the genetic information encoded in DNA. The genome is also a major physical entity of each cell; its large mass, dynamic properties, and unique structural features affect major cellular processes by nongenetic means. As a physical entity, the genome exerts mechanical forces onto its cellular environment via transmission from the nucleus to the cytoplasm, as well as within the nucleus between chromatin domains. Results from a broad range of experiments show that mechanical forces generated by the genome are critical contributors to a wide range of cellular processes and to cellular homeostasis. The chromatin fiber also serves as a physical binding scaffold both for proteins and for membranes, and it is increasingly evident that key cellular events, including faithful cell division, involve controlled interactions of large molecular protein complexes and membranes with the genetic material, independently of gene expression events. ADVANCES Recent findings in model systems as varied as yeast, flies, and humans reveal that genomes not only serve to control gene expression programs but also affect cellular functions by nongenetic means via their physical properties. Prominent examples of nongenetic functions of the genome include its role as a physical scaffold to support the assembly of the nuclear membrane and the nuclear pore complex, thereby facilitating the formation of a functional nuclear envelope. In addition, the physical mass of condensed chromatin at the nuclear periphery strengthens the nuclear envelope and enhances the ability of cells and nuclei to withstand mechanical forces exerted by the environment; this function is critical during cell migration or in tissues exposed to mechanical stress, such as the continuously beating heart. Furthermore, the genome serves as an anchoring platform for signaling molecules that regulate vital cellular processes, such as the controlled sequestration of cell cycle checkpoint proteins and of factors involved in licensing cells for cytokinesis. The physical organization of the genome also functions to alert and activate the DNA damage response machinery, whose proper functioning is crucial for preventing malignancies and seems necessary for the initiation of the cell cycle. At the level of tissue organization, an intriguing nongenetic function of the genome is in determining the optical properties of rod cells in the retina of nocturnal animals, thereby enhancing their night vision. OUTLOOK The realization that the genome acts via nongenetic mechanisms greatly expands our understanding of its biological importance. It is increasingly clear that the genome’s large mass and dynamic properties play a critical role in biological processes that ultimately regulate cell function and organismal survival, such as the cellular response to mechanical forces, the propagation of the cell cycle, the ability of the cell to divide, and the ability of cells to migrate. These emerging nongenetic functions of the genome are largely unexplored, and it is likely that they affect a wider range of cellular processes than currently realized. To characterize the known nongenetic functions of the genome as well as to discover new ones, it will be essential to develop methods to measure the physical properties of genomes in intact cells. Even more important will be the establishment of techniques to specifically and precisely manipulate physical features of the genome. These lines of investigation have the potential to uncover the full spectrum of nongenetic mechanisms by which the genome affects cellular processes, and to elucidate the interplay of genetic and nongenetic genome events, ultimately leading to a more complete understanding of the complexity of genome function. Genetic and nongenetic functions of the genome. In the interphase nucleus (center), the genome is organized into domains; shown is the domain organization of chromosomes in the nucleus. The well-established genetic functions of genomes (bottom) are the maintenance and transmission of genetic information and the expression of genetic programs. Nongenetic functions of the genome (top) include nuclear assembly, response to mechanical forces, cell migration, intra- and extranuclear signaling, and, at the physiological level, enhanced nocturnal vision. The primary function of the genome is to store, propagate, and express the genetic information that gives rise to a cell’s architectural and functional machinery. However, the genome is also a major structural component of the cell. Besides its genetic roles, the genome affects cellular functions by nongenetic means through its physical and structural properties, particularly by exerting mechanical forces and by serving as a scaffold for binding of cellular components. Major cellular processes affected by nongenetic functions of the genome include establishment of nuclear structure, signal transduction, mechanoresponses, cell migration, and vision in nocturnal animals. We discuss the concept, mechanisms, and implications of nongenetic functions of the genome.