Epigenetic control: slow and global, nimble and local (original) (raw)

Chromatin and epigenetic features of long-range gene regulation

Nucleic Acids Research, 2013

The precise regulation of gene transcription during metazoan development is controlled by a complex system of interactions between transcription factors, histone modifications and modifying enzymes and chromatin conformation. Developments in chromosome conformation capture technologies have revealed that interactions between regions of chromatin are pervasive and highly cell-type specific. The movement of enhancers and promoters in and out of higher-order chromatin structures within the nucleus are associated with changes in expression and histone modifications. However, the factors responsible for mediating these changes and determining enhancer:promoter specificity are still not completely known. In this review, we summarize what is known about the patterns of epigenetic and chromatin features characteristic of elements involved in long-range interactions. In addition, we review the insights into both local and global patterns of chromatin interactions that have been revealed by the latest experimental and computational methods. ELEMENTS OF TRANSCRIPTIONAL CONTROL IN VERTEBRATES Promoters and proximal elements A promoter is the genomic region overlapping the transcription start sites (TSSs) of a gene. Because of the precision with which TSSs can be identified, especially using CAGE technology (10), this class of regulatory elements has been well studied in comparison with other classes.

Inheritance of epigenetic chromatin silencing

Journal of Theoretical Biology, 2009

Maintenance of alternative chromatin states through cell divisions pose some fundamental constraints on the dynamics of histone modifications. In this paper, we study the systems biology of epigenetic inheritance by defining and analyzing general classes of mathematical models. We discuss how the number of modification states involved plays an essential role in the stability of epigenetic states. In addition, DNA duplication and the consequent dilution of marked histones act as a large perturbation for a stable state of histone modifications. The requirement that this large perturbation falls into the basin of attraction of the original state sometimes leads to additional constraints on effective models. Two such models, inspired by two different biological systems, are compared in their fulfilling the requirements of multistability and of recovery after DNA duplication. We conclude that in the presence of multiple histone modifications that characterize alternative epigenetic stable states, these requirements are more easily fulfilled.

Chromatin dynamics rule the genome

Genome biology, 2005

Changes in chromatin are important in the regulation of gene expression, and chromatin structure can be altered by nucleosome remodeling, modification of histone tails, or replacement of canonical histones by histone variants. A recent FASEB meeting on chromatin and transcription in Colorado covered a broad range of topics, including histone modifications, transcriptional regulation, histone variants, chromatin boundaries and higher-order structures. This report highlights just a few of the novel findings discussed at the meeting.

The Epigenetics of Gene Transcription and Higher Order Chromatin Conformation

2006

ABBREVIATIONS 8. Long-range chromatin interactions and disease AIMS OF THE PRESENT STUDY RESULTS AND DISCUSSION CONCLUDING REMARKS a distance less than 100-300 nm from transcribing regions of the Hbb-b1 and Hbb-b2 globin genes. Another study strongly supported tracking along the DNA [7]. In this study chromatin immunopurification was used to show that that factors associate with the enhancer, subsequently leave it and track along the DNA to reach the promoter in vivo. An elegant study carried out on HNF-4 promoter-enhancer further supported the facilitated-tracking or looping-tracking models [6].The researchers studied the order of recruitment of factors to the HNF-4 regulatory regions upon the initial activation of the gene during enterocyte differentiation. Initially, an independent assembly of regulatory complexes at the proximal promoter and the upstream enhancer regions was observed which was subsequently followed by the tracking of the entire DNA-protein complex formed on the enhancer along the intervening DNA until it encountered the proximal promoter. This movement correlated with a unidirectional spreading of histone hyperacetylation. The properties of Drosophila CHIP protein provided support for linking (spreading-looping) model. Interestingly, CHIP cannot bind to DNA directly, but can interact with numerous transcription factors and facilitate their action over a distance in vivo [8, 9]. It was proposed that CHIP is recruited by an activator protein bound at an enhancer; which then works as a protein "bridge" between the activator bound at the enhancer and other proteins having multiple weak/non-binding sites between the enhancer and promoter [10, 11]. As a result, a wave of small protein-stabilized chromatin loops is initiated at the enhancer and moves towards the promoter. DNA supercoiling and enhancer-promoter communication: Extensive studies in prokaryotes led to the proposal of two mechanisms to explain how DNA supercoiling can facilitate enhancer-promoter communication over large distances: "Slithering" and "Branch Collision" [12, 13] (Fig 3).The 'slithering model' suggests that intertwined DNA helixes can slide relative to each other on super coiled DNA at a high rate and this sliding greatly increases the probability of enhancer-promoter getting in close proximity. Alternatively, according to 'branch collision model', frequent collisions between the branches formed on super coiled DNA could facilitate communication between the enhancer and promoter localized on different branches of the same DNA molecule. The figure 3 depicts these models where enhancer and promoter are indicated by black and white boxes. Based on computer simulations of Brownian dynamics of super coiled DNA, it has been proposed that slithering is the predominant mechanism facilitating enhancerpromoter communication over distances up to 10 kb [14]. This is yet to be tested experimentally. Does DNA supercoiling facilitate enhancer-promoter communication in eukaryotes? The bulk of a eukaryotic genome does not contain unconstrained DNA supercoiling [15] and there is no enzyme (a gyrate) to generate it. However, there are several ways including nucleosome displacement or remodeling, transcript elongation [16, 17, 18, and 19] to generate negative supercoiling in eukaryotes. In support of this, transcriptionally active regions have been shown to contain considerable levels of unconstrained DNA supercoiling [20]. Moreover, DNA supercoiling is needed for the action of eukaryotic transcriptional and recombination enhancers over a large distance in vitro [21, 22].

Specificity, propagation, and memory of pericentric heterochromatin

2014

The cell establishes heritable patterns of active and silenced chromatin via interacting factors that set, remove, and read epigenetic marks. To understand how the underlying networks operate, we have dissected transcriptional silencing in pericentric heterochromatin (PCH) of mouse fibroblasts. We assembled a quantitative map for the abundance and interactions of 16 factors related to PCH in living cells and found that stably bound complexes of the histone methyltransferase SUV39H1/2 demarcate the PCH state. From the experimental data, we developed a predictive mathematical model that explains how chromatin-bound SUV39H1/2 complexes act as nucleation sites and propagate a spatially confined PCH domain with elevated histone H3 lysine 9 trimethylation levels via chromatin dynamics. This "nucleation and looping" mechanism is particularly robust toward transient perturbations and stably maintains the PCH state. These features make it an attractive model for establishing functional epigenetic domains throughout the genome based on the localized immobilization of chromatin-modifying enzymes.