Molecular basis and biological function of variability in spatial genome organization
Heterogeneity in genome organization How the genome is organized in the three dimensional space of the cell nucleus influences the activity of gene expression. Finn and Misteli review features of genome architecture and cell and allele specific variability in spatial genome organization. They also connect stochasticity in gene transcription and variability in genome organization and discuss the functional consequences of genome variability at the cell and population levels in development and disease. Science, this issue p. eaaw9498 BACKGROUND The eukaryotic genome is hierarchically organized in the cell nucleus into DNA loops, chromatin domains, compartments, and, ultimately, chromosomes. Many of the most prominent organizational features of genomes are highly reproducible on the population level and are evolutionarily conserved, suggesting functional relevance. Numerous organizational features, such as the location of a gene or promoter enhancer loops, have been implicated in the regulation of genome processes including transcription, replication, and repair. At the same time, single cell analysis has revealed extensive stochasticity of gene expression, with individual genes undergoing cycles of bursts in activity and periods of inactivity. Because gene activity is closely linked to features of genome organization, the extent of variability of genome organization at the single cell level has arisen as a question of interest. We review new findings that document extensive cell and allele specific variability of genome organization and discuss potential mechanisms of structural variability and its implications for genome function. ADVANCES Recent advances in genome mapping using single cell biochemical and imaging methods have enabled systematic probing of higher order genome organization at the level of individual cells. Results from these approaches validate observations from traditional population based methods but also reveal that genome organization is considerably more variable than anticipated. In particular, specific chromatin chromatin interactions appear to be present in only a relatively small fraction of cells in a population, and the genome organization at individual alleles in the same nucleus differs considerably. Furthermore, the internal shapes of structural features such as chromatin domains are fluid, and the genomic positions of the boundaries between chromatin domains vary from allele to allele. The highly variable nature of genome architecture points to a high degree of intrinsic noise in genome organization, in line with the observed stochasticity in gene expression. OUTLOOK The observed single cell heterogeneity in genome organization challenges the traditional view of gene regulation, which assumes that the epigenetic landscape controlling gene activity is largely stable. Rather, it now appears that both the structure and activity of genes are dynamic and stochastic. These probabilistic features of genome organization have implications for how long lasting cellular states are generated and how individual cells transition between states during physiological or pathological processes, in that they suggest that fluidity between cell states may be an underlying property of a population of cells. The extent and relevance of genome organization and function can be addressed experimentally using the wide arsenal of tools now available, including deep sequencing and single molecule imaging of chromatin. A key question is whether variability in structural features of chromatin causes the stochastic activity of individual genes, or vice versa. Furthermore, although it is likely that the dynamic motion of chromatin and the randomness introduced during cell division contribute to variability in genome architecture, their importance and their roles in generating genome heterogeneity have not been characterized. An intriguing and potentially far reaching possibility is that the variability of genome organization is cell type specific and actively regulated, which would add a novel layer of control to gene expression and genome function. Rather than implying that genome organization is not functionally relevant, the observed variation in genome organization suggests new mechanisms by which chromatin topology may affect cell function. Genome organizational plasticity and its potential functional role. Major features of genome organization, including individual chromatin chromatin contacts, loops, domains, and chromosome territories, are highly plastic, as is gene expression. Recent evidence suggests that this structural heterogeneity is stochastic and intrinsic to the DNA polymer and may be a functional and regulated feature of a cell. The complex three dimensional organization of genomes in the cell nucleus arises from a wide range of architectural features including DNA loops, chromatin domains, and higher order compartments. Although these features are universally present in most cell types and tissues, recent single cell biochemistry and imaging approaches have demonstrated stochasticity in transcription and high variability of chromatin architecture in individual cells. We review the occurrence, mechanistic basis, and functional implications of stochasticity in genome organization. We summarize recent observations on cell and allele specific variability of genome architecture, discuss the nature of extrinsic and intrinsic sources of variability in genome organization, and highlight potential implications of structural heterogeneity for genome function.
Science