A novel boundary element may facilitate independent gene regulation in the Antennapedia complex of Drosophila

Belozerov, Vladimir E.; Majumder, Parimal; Shen, Ping; Cai, Houjian

doi:10.1093/emboj/cdg297

Cited by 96 publications

(109 citation statements)

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“…In the case of the two homeotic gene clusters the Antennapedia complex (see Glossary, Box 1) and the Bithorax complex (see Glossary, Box 1), multiple regulatory regions control the segment-specific expression of homeotic genes (see below). Such a complex arrangement of segment-specific regulatory sequences argued for the presence of insulator sequences, which, again, was confirmed functionally (Hagstrom et al, 1996;Belozerov et al, 2003). Similarly, in vertebrates, the identification of complex expression patterns of adjacent genes or of neighbouring regulatory regions with different activities led to the prediction of insulators at these sites.…”

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confidence: 71%

“…Importantly, the linear arrangement of Hox genes on the chromosome reflects their expression along the body axis, a phenomenon called co-linearity. This arrangement of genes and of segment-specific regulatory sequences argued for the existence of insulator sequences that separate segment-specific regulatory units (Lewis, 1978;Hagstrom et al, 1996;Belozerov et al, 2003). Deletion of these insulator sequences results in a shift of segment identity, such that neighbouring segments show an identical identity (for details, see Maeda and Karch, 2006).…”

Section: Several Factors Including Ctcf Mediate Insulator Function mentioning

confidence: 99%

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CTCF: insights into insulator function during development

2012

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The genome of higher eukaryotes exhibits a patchwork of inactive and active genes. The nuclear protein CCCTC-binding factor (CTCF) when bound to insulator sequences can prevent undesirable crosstalk between active and inactive genomic regions, and it can also shield particular genes from enhancer function, a role that has many applications in development. Exciting recent work has demonstrated roles for CTCF in, for example, embryonic, neuronal and haematopoietic development. Here, we discuss the underlying mechanisms of developmentally regulated CTCF-dependent transcription in relation to model genes, and highlight genome-wide results indicating that CTCF might play a master role in regulating both activating and repressive transcription events at sites throughout the genome. Key words: Igf2/H19, Cohesin, Homeotic gene, Imprint, Insulator IntroductionAs early as the 1950s, the existence of genomic insulators has been postulated based on several observations, such as the phenomenon of position effect variegation (see Glossary, Box 1), in which gene activity is dependent on its genomic location (Lewis, 1950). These locations were later identified as heterochromatic, or inactive, chromatin regions, which, upon translocation, inversion or deletion of chromosomal fragments, may repress the expression of a neighbouring gene (Baker, 1968). The interpretation of this observation was that the genomic rearrangement might have deleted insulators that normally protect genes from the repressive effect of flanking heterochromatin. To add weight to this notion, the biophysical analysis of the Drosophila genome argued for the presence of insulator sequences that separate supercoiled genomic domains (Benyajati and Worcel, 1976). More recently, functional tests with transgenes (see Glossary, Box 1) revealed the existence of three properties of insulators (see Glossary, Box 1): (1) to provide a barrier (or boundary; see Glossary, Box 1) function to prevent repressive heterochromatin from spreading into a neighbouring domain; (2) to provide an enhancer-blocking (see Glossary, Box 1) function when positioned between the enhancer and promoter (see Glossary, Box 1) (Sun and Elgin, 1999), allowing insulators to produce opposite effects either by facilitating the maintenance of a transcriptionally active state or by inhibiting the action of enhancers; (3) to allow three-dimensional looping of genomic regions, a property that is possibly inherent to insulator function, as discussed throughout this review.The first proteins identified that bind to insulator sequences and mediate the insulating function were boundary element-associated factor of 32 kDa (BEAF32) (Zhao et al., 1995), Su(Hw) (Holdridge and Dorsett, 1991;Geyer and Corces, 1992) and zeste-white 5 (Zw5; dwg -FlyBase) (Gaszner et al., 1999) in Drosophila. In vertebrates, CCCTC-binding factor (CTCF) was first shown to mediate insulation (Bell et al., 1999) and was later demonstrated to be highly conserved and also found in Drosophila (dCTCF) (Moon et al., 2005). The DNA-binding do...

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confidence: 71%

Section: Several Factors Including Ctcf Mediate Insulator Function mentioning

confidence: 99%

CTCF: insights into insulator function during development

2012

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“…For example, such a role has been suggested for GAF in the case of Fab-7 and SF1 insulators, which have many GAF binding sites. 45,46 Thus, further studies are necessary for elucidating the role of BTB domains of the ttk group in longdistance interactions and their other possible activities in transcriptional regulation.…”

Section: Discussionmentioning

confidence: 99%

Drosophila BTB/POZ Domains of “ttk Group” Can Form Multimers and Selectively Interact with Each Other

Bonchuk

Denisov

Georgiev

et al. 2011

Journal of Molecular Biology

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Edited by M. GottesmanKeywords: GAGA; BTB domain; Mod(mdg4); CP190; chromatin insulatorThe BTB (bric-a-brac, tramtrack and broad complex)/POZ (poxvirus and zinc finger) domain is a conserved protein-protein interaction motif contained in a variety of transcription factors involved in development, chromatin remodeling, insulator activity, and carcinogenesis. All wellstudied mammalian BTB domains form obligate homodimers and, rarely, tetramers. Only the BTB domain of the Drosophila GAGA factor (GAF) has been shown to exist as higher-order multimers. The BTB domain of GAF belongs to the "ttk group" that contains several highly conserved sequences not found in other BTB domains. Here, we have shown by size-exclusion chromatography, chemical cross-linking, and nondenaturing PAGE that four additional BTB domains of the ttk group-Batman, Mod(mdg4), Pipsqueak, and Tramtrack-can form multimers, like GAF. Interestingly, the BTB domains of GAF and Batman have formed a wide range of complexes and interacted in the yeast two-hybrid assay with other BTB domains tested. In contrast, the BTB domains of Mod(mdg4), Pipsqueak, and Tramtrack have formed stable high-order multimer complexes and failed to interact with each other. The BTB domain of Drosophila CP190 protein does not belong to the ttk group. This BTB domain has formed stable dimers and has not interacted with domains of the ttk group. Previously, it was suggested that GAF oligomerization into higher-order complexes facilitates long-range activation by providing a protein bridge between an enhancer and a promoter. Unexpectedly, experiments in the Drosophila model system have not supported the role of GAF in organization of longdistance interaction between the yeast GAL4 activator and the white promoter.© 2011 Elsevier Ltd. All rights reserved. IntroductionThe BTB (bric-a-brac, tramtrack and broad complex) domain [also known as the POZ (poxvirus and zinc finger) domain] is a versatile protein-protein interaction motif that participates in a wide range of cellular functions, including transcription regulation (for review, see Ref. 1 ). Transcription factors with a BTB domain at the N-terminus comprise a large important class of molecules involved in development and carcinogenesis. As shown in crystallographic studies,

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“…[26][27][28][29][30][31] Two additional proteins, centrosomal protein 190 (CP190) and Mod(mdg4), do not bind DNA; instead, they interact with the insulator DNA-binding proteins and with themselves to mediate inter/intra-chromosomal interactions. [32][33][34][35] Analysis of the genome-wide distribution of these proteins has given some insights into the issue of whether the different Drosophila insulators play distinct or overlapping roles in genome organization and function.…”

Section: Introductionmentioning

confidence: 99%