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Review
. 2016 Sep:57:24-30.
doi: 10.1016/j.semcdb.2015.11.013. Epub 2015 Dec 3.

Towards a predictive model of chromatin 3D organization

Chenhuan Xu  1 , Victor G Corces  2
Affiliations
Review

Towards a predictive model of chromatin 3D organization

Chenhuan Xu et al. Semin Cell Dev Biol. 2016 Sep.

Abstract

Architectural proteins mediate interactions between distant regions in the genome to bring together different regulatory elements while establishing a specific three-dimensional organization of the genetic material. Depletion of specific architectural proteins leads to miss regulation of gene expression and alterations in nuclear organization. The specificity of interactions mediated by architectural proteins depends on the nature, number, and orientation of their binding site at individual genomic locations. Knowledge of the mechanisms and rules governing interactions among architectural proteins may provide a code to predict the 3D organization of the genome.

Keywords: Architectural proteins; CTCF; Nucleus; Transcription.

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Figures

Figure 1
Figure 1
Organization of architectural proteins in different organisms. The main architectural protein in yeast is TFIIIC, which is able to recruit both cohesin and condensin. Drosophila has a large number of DNA-binding architectural proteins that bind to specific sequences in the genome and recruit a series of accessory proteins. Some of these DNA-binding proteins colocalize with other architectural proteins that recognize DNA sequences in close proximity, forming APBSs of varied occupancy. CTCF is the best characterized DNA-binding architectural protein in vertebrates but several other DNA-binding proteins have been shown to colocalize with CTCF and may also play an architectural role to ether enhancer or modify the ability of CTCF to establish interactions between distant sites in the genome.
Figure 2
Figure 2
The role of architectural proteins in the formation of TADs. The figure shows a cartoon representation of a Hi-C heatmap showing 3 TADs. Each TAD has a variable number of sub-TADs indicated by darker red tones inside the TADs. Architectural proteins (shown as spheroids or tori of different colors) are present at APBSs located at the borders of TADs and sub-TADs. Based on results obtained in Drosophila, APBSs with high architectural protein occupancy are located at strong TAD borders, whereas lower occupancy APBSs are found at weak TAD or sub-TAD borders. Although this correlation is also found in mammals, it is not as strong as in Drosophila. In mammals the orientation of CTCF binding sites (shown by red arrowheads) also contributes to the establishment of interactions leading to the formation of TADs and sub-TADs. Although divergently-oriented CTCF sites are enriched at TAD borders, it is unclear whether this is also the case at sub-TADs. It is not currently understood what distinguishes TAD and sub-TAD borders in vertebrate cells.
Figure 3
Figure 3
Models to explain the preferential establishment of interactions between divergent CTCF sites. A. Cohesin associates with a randomly located genomic site, and initiates the formation of a loop. Cohesin then extrudes a progressively larger loop until it becomes halted at a boundary element, potentially formed by interactions between cohesin and CTCFs with a particular orientation [61]. B. CTCF binds to its recognition sequence and bends the DNA, thus initiating the formation of a loop. CTCF-bound cohesin is then able to extrude a loop by pulling one of the DNA strands. The process stops when a CTCF-bound site in a convergent orientation interacts with the site where the loop was initiated. This interaction is mediated by the two CTCF proteins, which cannot interact when in divergent orientation.
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