A hypothesis for chromatin domain opening

Abstract

SummaryThe eukaryotic genome is organized into different domains by cis-acting elements, such as boundaries/ insulators and matrix attachment regions, and is packaged with different degrees of condensation. In the M phase, the chromatin becomes further highly condensed into chromosomes. The first step for transcriptional activation of a given gene, at a particular time during development, in any locus, is the opening of its chromatin domain. This locus needs to be kept in this state in each early G 1 phase during every cell cycle. Certain distal enhance elements, including locus control regions (LCRs) and enhancers, are believed to perform this target chromatin domain opening process and several models have been proposed to explain distal enhance action. But they did not explain precisely how a given chromatin domain is opened. Based on various studies, we propose a hypothesis for the mechanism of opening chromatin on a large scale. One important mechanism may involved breaking one or two DNA strands and reducing the linking numbers within chromatin domain. The topological changes can overpass some complexes formed on DNA strands and can be transmitted from specific localized points over a broad region, until boundary elements or insulators are reached. These may initiate downstream events such as propagation of histone acetylation and the binding of transcription factors to proximal promoters and may further augment the action mediated by distal enhancer elements.

Boundary elements and nuclear organization

“…Perhaps, the lack of a transcription unit between two boundary elements prevents their proper organization or targeting, resulting in such "unproductive" pairing. Alternatively, it has been suggested that structural domains created by insulators are topologically restrictive, implying that enhancers propagate some type of topological change or require conformational freedom to activate promoters (Xin et al, 2003). One insulator is able to block this topological change, while two closely positioned insulators may pair and effectively create a topologically closed domain, which can be circumvented.…”

“…Finally, another potential scenario for an insulator-driven disruption of enhancer-promoter communication is that the enhancer-generated signal is stopped by the physical divide created by boundary elements. Recently, topological change, such as negative supercoiling density or conformational change in the DNA, has been proposed as a possible enhancer-directed signal and a determining factor for organization of chromatin domains (Xin et al, 2003). One appealing aspect of this explanation is that it can theoretically unite the tracking and the looping models of enhancer action-the enhancer-generated supercoiling can be propagated down the chromatin fiber and simultaneously, result in a more global looping of DNA.…”

Suppression by p38 MAP Kinase Inhibitors (Pyridinyl Imidazole Compounds) of Ah Receptor Target Gene Activation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin and the Possible Mechanism

“…Recently, Ke and co-workers noted that histone acetylation of the Cyp1a1 promoter, especially the TATA box region, was suppressed by treatment with LPS (11). There is much evidence that histone molecules tend to be acetylated in the chromatin of the promoter region of the target gene before the transcription of its mRNA, and the subsequent alteration in the chromatin structure gives transcription factors easy access to the promoter region (37). In the case of .…”

Insulator dynamics and the setting of chromatin domains

“…may also be seen as simple topological barriers that would arrest the propagation of topological changes associated with long-range chromatin folding or unfolding. (32,33) (2) In the active, antisilencing model ( Fig. 2b), the insulator directly interferes with the mechanism of heterochromatin formation or maintenance by serving as an entry site for enzymatic activities that either covalently modify chromatin, or modulate nucleosome properties, or affect DNA topology.…”