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. 2015 Nov;138 Pt 2(Pt 2):122-132.
doi: 10.1016/j.mod.2015.07.002. Epub 2015 Jul 26.

The boundary paradox in the Bithorax complex

Olga Kyrchanova  1 , Vladic Mogila  2 , Daniel Wolle  3 , Jose Paolo Magbanua  4 , Robert White  4 , Pavel Georgiev  5 , Paul Schedl  6
Affiliations

The boundary paradox in the Bithorax complex

Olga Kyrchanova et al. Mech Dev. 2015 Nov.

Abstract

The parasegment-specific expression of the three Drosophila Bithorax complex homeotic genes is orchestrated by nine functionally autonomous regulatory domains. Functional autonomy depends upon special elements called boundaries or insulators that are located between each domain. The boundaries ensure the independent activity of each domain by blocking adventitious interactions with initiators, enhancers and silencers in the neighboring domains. However, this blocking activity poses a regulatory paradox--the Bithorax boundaries are also able to insulate promoters from regulatory interactions with enhancers and silencers and six of the nine Bithorax regulatory domains are separated from their target genes by at least one boundary element. Here we consider several mechanisms that have been suggested for how the Bithorax regulatory domains are able to bypass intervening boundary elements and direct the appropriate parasegment-specific temporal and spatial expression of their target gene.

Keywords: Bithorax complex; Boundary bypass; Boundary element; Enhancer blocking; Insulator.

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Figures

Figure 1
Figure 1. The Bithorax Complex
(A) Map and coordinates of the BX-C are taken from the FlyBase genome browser D. melanogaster (R6.04). Multicolored boxes above illustrate the embryo parasegments (PS) corresponding to the segments of the adult fly. The same color brackets indicate localization of regulatory domains that control expression of the BX-C genes Ubx, abd-A, and Abd-B (shown as black horizontal arrows). Abd-B has different promoters designated as m and r. The expression patterns of each BX-C gene are shown and the colored bar indicates the regulatory domains according to Maeda and Karch (2006) (darker shades of color indicate higher expression levels). The Ubx, abd-A, and Abd-B regulatory domains are organized into the three transcriptionally associated regulatory domains (TARDs), and the three TARDs are designated by yellow, blue, and green brackets, respectively. Insulators identified in BX-C in ChIP experiments are shown as upward arrows: red – for those that are bound by dCTCF and blue – for the one CTCF-independent insulator, Fab-7. Insulators whose identity has been confirmed by mutations or functional assays are underlined and labeled by color font. Insulators identified only on the basis of ChIP experiments are labeled with black font. Abd-BI (AB-I) is an insulator-like element located upstream of the Abd-Bm promoter. In addition to being associated with known insulator proteins, it functions in bypass assays with other boundaries from the Abd-B TARD (Kyrchanova et al., 2011). The Fub-2 insulator is located downstream of the Ubx transcription unit and is identified on the basis of its association with known insulator proteins. (B) A model for the sequential activation of BX-C regulatory domains going from more anterior to more posterior parasegments (Peifer et al., 1987; Mihaly et al., 2006; Bowman et al., 2014). The model shows the sequential activation of the regulatory domains in the Abd-B TARD. Stars symbolize initiators, the ovals – tissue specific enhancers (for simplicity only one enhancer is shown; however, there may be several stage/tissue specific enhancers in each domain). Activation of successive initiators by position dependent gap and pair rule genes is indicated by the green (light, intermediate and dark) parasegment “position signals.” Each domain has a maintenance element (rectangles on the left side of the regulatory domain). These maintenance elements can be set in the repressive state by the parasegment-specific initiation. In this case the Polycomb complexes assemble on the maintenance element (grey rectangles) and silence the domain (indicated by light grey “repressive chromatin” across the domain). Alternatively, the maintenance elements can be set in the active state (pink rectangles). In this case, TrxG proteins bind to the maintenance element (pink rectangles) and keep the domain in an active state. In the active state the various enhancers in the domain can regulate the target Abd-B promoter. Domains are insulated from each other by boundary elements (upward arrows).
Figure 2
Figure 2. Insulator-insulator interactions and insulator bypass
This diagram illustrates a transgene assay for insulator bypass. The enhancer is shown as a red circle. The two reporter genes in the transgene are indicated by yellow and grey lines with arrowheads. The two insulators in the transgene are indicated by thick green arrows, while the factors that associate with the insulators and mediate pairing interactions are indicated by colored circles and boxes. Note that the orientation of the insulators in A and B is different. The insulators in A are arranged in opposite orientations, while the insulators in B are in the same orientation. Interactions between insulators in the A and B transgenes generate loops with different topological configurations. (A) Head-to tail pairing of insulators in the opposite orientation configures the intervening loop in a manner that brings the enhancer (red circle) into a close proximity to the promoter driving expression of the grey reporter. Activation of the grey reporter is illustrated by the change in color to red. (B) In this transgene, head-to-tail pairing of insulators in the same orientation generates a loop in which the enhancer is far from the promoter of the grey reporter. In this case, the enhancer doesn’t activate the reporter expression. Note that in both the A and B configurations, the yellow reporter is not activated by the upstream enhancer.
Figure 3
Figure 3. gypsy transposon insertions in the Ubx region of BX-C
This figure shows a map of the Ubx region of BX-C and includes the Ubx transcription unit and the two Ubx regulatory domains, abx/bx and bxd/pbx. The numbered line represents the BX-C DNA walk in kilobases from its starting point as in Bender et al., 1983a. Triangles indicate the sites of insertion of mutations that are associated with gypsy transposon insertions. Vertical small yellow ovals designate enhancers, blue rectangles – PRE elements.
Figure 4
Figure 4. The open-gate model
This figure shows the coupling of insulator inactivation with the successive activation of BX-C regulatory domains going from anterior to posterior parasegments. The top track shows the Ubx and abd-A genes and their associated regulatory domains with coordinates according to Martin et al., 1995. Enhancers are designated as ovals with different shades: yellow and dark-yellow represent enhancers in abx/bx and bxd/pbx, respectively, that direct Ubx expression in PS5 and PS6; pale-blue, blue and deep blue represent enhancers in iab-2, iab-3, and iab-4, respectively, that direct abd-A expression in PS7-9. The location of insulators between the regulatory domains is indicated by arrows. Active insulators in each parasegment are shown by arrows that are colored red, while insulators that have been neutralized are indicated by unfilled black arrows. Small grey circles designate repressive chromatin status.
Figure 5
Figure 5. The insulator bypass model
This figure depicts insulator bypass in the Abd-B TARD. The top track shows the four regulatory domains in the Abd-B TARD and Abd-Bm promoter. Insulators are shown as vertical rectangles with the same color as the enhancers (ovals) whose function they facilitate. In PS10, where the iab-5 regulatory domain is active, the Fab-6 insulator interacts with the insulator-like element, Abd-BI (AB-I), located upstream of the Abd-Bm promoter. This brings iab-5 enhancers to the promoter. In PS11, interactions between the Fab-7 insulator and Abd-BI brings the iab-6 enhancers to the Abd-Bm promoter. Insulators of active domains are marked by red, and insulators that interact with Abd-BI marked by bold. The blue zone symbolizes the repressive domain. All elements outside of the blue zone are active.
Figure 6
Figure 6. The parasegment-specific architectural element in abx/bx
The top track shows the map of the Ubx regulatory domain with coordinates according to Martin et al., 1995. dCTCF binding sites are marked as red upward arrows. The parasegmentally regulated dCTCF binding site is marked by an open arrow with an asterisk underneath; dCTCF does not bind to this site in PS3 where Ubx is turned off. However, in PS5 where the Ubx gene is turned on, dCTCF binds to the parasegmentally regulated site and can mediate interactions with architectural elements in a close proximity to the Ubx promoter. This interaction brings the abx enhancers in contact with the Ubx promoter.
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References

    1. Bantignies F, Grimaud C, Lavrov S, Gabut M, Cavalli G. Inheritance of Polycomb-dependent chromosomal interactions in Drosophila. Genes Dev. 2003;17:2406–2420. - PMC - PubMed
    1. Barges S, Mihaly J, Galloni M, Hagstrom K, Müller M, Shanower G, Schedl P, Gyurkovics H, Karch F. The Fab-8 boundary defines the distal limit of the bithorax complex iab-7 domain and insulates iab-7 from initiation elements and a PRE in the adjacent iab-8 domain. Dev. Camb. Engl. 2000;127:779–790. - PubMed
    1. Beachy PA, Helfand SL, Hogness DS. Segmental distribution of bithorax complex proteins during Drosophila development. Nature. 1985;313:545–551. - PubMed
    1. Bender W, Akam M, Karch F, Beachy PA, Peifer M, Spierer P, Lewis EB, Hogness DS. Molecular Genetics of the Bithorax Complex in Drosophila melanogaster. Science. 1983;221:23–29. - PubMed
    1. Bender W, Hudson A. P element homing to the Drosophila bithorax complex. Dev. Camb. Engl. 2000;127:3981–3992. - PubMed

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