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Long-Range Repression in the Drosophila Embryo HAINI N Proc. Natl. Acad. Sci. USA Vol. 93, pp. 9309-9314, September 1996 Colloquium Paper This paper was presented at a colloquium entitled "Biology of Developmental Transcription Control, " organized by Eric H. Davidson, Roy J. Britten, and Gary Felsenfeld, held October 26-28, 1995, at the National Academy of Sciences in Irvine, CA. Long-range repression in the Drosophila embryo HAINI N. CAI, DAVID N. ARNOSTI, AND MICHAEL LEVINE* Department of Biology, Center for Molecular Genetics, Pacific Hall, University of California at San Diego, La Jolla, CA 92093-0347 ABSTRACT Transcriptional repressors can be character- Short-range transcriptional repression appears to account ized by their range of action on promoters and enhancers. for enhancer autonomy in a modular promoter. Repressors Short-range repressors interact over distances of50-150 bp to bound to a given enhancer do not interfere with the activators inhibit, or quench, either upstream activators or the basal contained within neighboring enhancers. For example, the transcription complex. In contrast, long-range repressors act posterior border of eve stripe 3 is established by the gap over several kilobases to silence basal promoters. We describe repressor knirps (kni; ref. 7), which is a member of the nuclear recent progress in characterizing the functional properties of receptor superfamily, and is expressed in the presumptive one such long-range element in the Drosophila embryo and abdomen in early embryos (8). There are at least five kni- discuss the contrasting types of gene regulation that are made binding sites in the stripe 3 enhancer, two of which map within possible by short- and long-range repressors. 100 bp of critical d-STAT activator sites within the enhancer (9). The range of kni repression activity was investigated by Complex patterns of gene expression in the Drosophila embryo inserting synthetic kni-binding sites into a well-defined heter- are specified by spatially localized activators and repressors. ologous enhancer, the rhomboid lateral stripe enhancer ("rho Mechanisms of transcriptional activation are beginning to be NEE"). The rho NEE is repressed in abdominal regions of elucidated, but repression mechanisms are still poorly under- transgenic embryos when kni-binding sites are placed within stood. A combination of genetic, molecular, and biochemical 50-100 bp of the activator sites. However, when the kni sites approaches have begun to address this issue. Several types of are separated by 150 bp from the nearest NEE activators, they transcriptional repression have been proposed (1, 2), including are ineffective in mediating repression (10). These and other direct competition of repressors and activators for common observations prompted the proposal that kni is a short-range binding sites to DNA, local "quenching" of upstream activa- repressor that functions in a local fashion to inhibit, or quench, tors or the basal transcription complex, and long-range inter- nearby activators within the enhancer to which it is bound. In actions between repressors and the basal apparatus. The principle, this type of repression can permit enhancer auton- emerging picture is that some factors mediate "short-range" omy, as summarized in Fig. 1 Upper. A synthetic modular repression, interfering with transcriptional activators bound promoter containing the eve stripe 3 enhancer and rho NEE within 50-150 bp, whereas other "long-range" repressors are directs an additive pattern of expression because rho NEE capable of interfering with promoter function over long dis- activators are located beyond the range of kni repressors tances (see Fig. 1). As we discuss below, one such long-range bound to the stripe 3 enhancer (10). repressor complex, the ventral repression element (VRE) Similar experiments suggest that other spatially localized from the zerknullt (zen) gene, appears to silence the transcrip- repressors function only over short distances and permit tion complex over a distance of several kilobases. enhancer autonomy in a modular promoter. Examples include Drosophila promoters are often modular and contain a series Kruppel, which defines the posterior border ofeve stripe 2, and of nonoverlapping enhancers, which function independently of snail, which is responsible for excluding rho NEE expression one another to of from the ventral mesoderm (11, 12). Both Kruppel and snail generate composite patterns gene expres- to function over distances to kni. All sion. The segmentation gene, even-skipped (eve) contains a appear comparable three modular promoter. It encodes a repressors must map within -100-150 bp from the activators homeodomain protein that is that they quench. This requirement for close spacing ensures essential for the subdivision of the embryo into a repeating enhancer because enhancers are series of eve autonomy neighboring gen- body segments (3, 4). is transcribed in a series of erally beyond the range of repression. It is possible to "force" seven transverse stripes along the length of precellular em- a short-range repressor to block two enhancers. For example, bryos, foreshadowing overt segmentation of the germ band by as discussed above, the eve stripe 2 and stripe 3 enhancers are several hours (5). The expression of at least some of the stripes normally separated by a 1.7-kb spacer sequence. When this are regulated by separate enhancers in the eve promoter spacer is removed, the proximal-most Kruippel-binding site region. For example, stripe 3 is regulated by a 500-bp enhancer within the stripe 2 enhancer now maps within 150 bp of stripe located -3 kb upstream of the eve transcription start site (6). 3 activators. As a result, Kruppel not only represses the In contrast, stripe 2 is regulated by a separate 500-bp enhancer posterior border of stripe 2, but also attenuates the expression located - 1 kb from the start site. The stripe 2 and stripe 3 of stripe 3 (13). enhancers are separated by a 1.7-kb "spacer" sequence in the In contrast with the short-range repression discussed above, eve promoter region. A major goal of our recent studies has long-range repression works in a dominant fashion over dis- been to determine how these two enhancers function inde- tances of several kilobases. Such repression has been observed pendently of one another to generate a multistripe pattern of in a number of systems. For example, a long-range repression expression in early embryos. Abbreviations: VRE, ventral repression element; MSE, minimal stripe The publication costs of this article were defrayed in part by page charge enhancer; kni, knirp. payment. This article must therefore be hereby marked "advertisement" inI *To whom reprint requests should be addressed. e-mail: levine@ accordance with 18 U.S.C. §1734 solely to indicate this fact. jeeves.ucsd.edu. 9309 Downloaded by guest on September 29, 2021 9310 Colloquium Paper: Cai et al. Proc. Natl. Acad. Sci. USA 93 (1996) Short-range repression A I- co Long-range repression VRE MSE r h\\\\\\\\\\l LI I-- eve/lacZ 4D~ 11 B FIG. 1. Short- and long-range repression. (Upper) A short-range repressor (circle with spiral) locally represses activators (ovals) on enhancer 1, inhibiting this element's activity. Activators in enhancer 2 are not affected, allowing enhancer 2 to activate the gene. (Lower) A long-range repressor (circle with spiral) bound to enhancer 1 domi- nantly represses the transcription complex and blocks both enhancers. element establishes the rhombomere-specific pattern of MSE -. VRE within hindbrain of mouse Hoxb-1 expression the the embryo taiaii I'.rxxxxxxxxxxx.- % \\\ (14). Here we present evidence for a Drosophila long-range eve/ I acZ repressor, which appears to be distinct from short-range repressors such as snail and Kriippel. The promoter region of C the zen gene directs a simple on/offpattern of expression in the early embryo. zen is activated by one or more ubiquitously distributed factors and is repressed in ventral and lateral regions by the rel-related transcription factor, dorsal (dl). In a number of contexts, such as the rho NEE, dl acts as a transcriptional activator. However, in the context of the zen promoter, dl functions as a repressor. Previous studies have shown that dl binds near one or more "corepressor" sites within a distal region of the zen promoter (15-17). This distal sequence, the VRE, is located between -1.6 and -1.0 kb MSE VRE upstream of the zen transcription start site (Fig. 2). It contains three high-affinity dl-binding sites, as well as closely linked eve/latZ corepressor sites. Several lines of evidence suggest that the zen VRE functions FIG. 3. The zen VRE represses a heterologous enhancer over a as a dominant the exact of long distance. RNAs were detected by whole-mount in situ hybridiza- repressor element, although range tion, using a digoxigenin-labeled lacZ antisense RNA probe (6). repression was not established (15-17). The 600-bp VRE can Drosophila embryos were transformed by P-element-mediated germ- line transformation as described in ref. 6. Embryos are oriented with ZEN VENTRAL REPRESSION ELEMENT anterior to the left and dorsal up. (A-C) Early nuclear cycle 14 embryos containing VRE 600-MSE eve lacZ fusion genes. (A) zen VRE 600 is placed 5' of the fusion gene. Early expression includes a N D1 D2 D3 XPn broad stripe 2 band in the anterior that is ventrally repressed by the oA2 A3 -1 .6 -1.0 i VRE 600, superimposed on the dorsal staining-mediated by general AT1 AT2 AT3 activator sequences present in the zen VRE (16, 18). MSE, minimal stripe enhancer. (B and C) zen VRE 600 placed downstream of the lacZ coding region in the forward (B) and reverse (C) orientation. The VRE600 pattern of ventral repression is comparable to that of A. repress the ventral and lateral expression of various heterol- VRE200 ogous promoters and enhancers. For example, when placed immediately upstream of the eve stripe 2 enhancer, the VRE FIG.
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