The insulator functions of the<i>Drosophila</i>polydactyl C2H2 zinc finger protein CTCF: Necessity versus sufficiency

Kyrchanova, Olga; Maksimenko, Oksana; Ibragimov, A. N.; Sokolov, Vladimir; Postika, Nikolay; Lukyanova, M. B.; Schedl, Paul; Georgiev, Pavel

doi:10.1126/sciadv.aaz3152

Cited by 34 publications

(53 citation statements)

References 41 publications

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“…3g). These results suggest that, depending on the locus, CTCF may directly repress or activate the transcription of nearby genes, or alternatively CTCF may shield promoters from inappropriate enhancers or silencers as observed at Hox gene loci 21,40 .…”

Section: Ctcf Impacts Expression Patterns Of Genes Near Ctcf Peaksmentioning

confidence: 81%

“…CTCF occupancy scales with enhancer-blocker activity in a reporter assay. Previous studies of the functionality of CTCF binding sites stably integrated into the fly genome suggested that most of them lack insulator activity (i.e., the ability to block regulatory crosstalk) 36 , at least in single copies 40 . Here, we tested CTCF peaks in a quantitative reporter assay.…”

Section: Ctcf Impacts Expression Patterns Of Genes Near Ctcf Peaksmentioning

confidence: 99%

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CTCF loss has limited effects on global genome architecture in Drosophila despite critical regulatory functions

et al. 2021

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Vertebrate genomes are partitioned into contact domains defined by enhanced internal contact frequency and formed by two principal mechanisms: compartmentalization of transcriptionally active and inactive domains, and stalling of chromosomal loop-extruding cohesin by CTCF bound at domain boundaries. While Drosophila has widespread contact domains and CTCF, it is currently unclear whether CTCF-dependent domains exist in flies. We genetically ablate CTCF in Drosophila and examine impacts on genome folding and transcriptional regulation in the central nervous system. We find that CTCF is required to form a small fraction of all domain boundaries, while critically controlling expression patterns of certain genes and supporting nervous system function. We also find that CTCF recruits the pervasive boundary-associated factor Cp190 to CTCF-occupied boundaries and co-regulates a subset of genes near boundaries together with Cp190. These results highlight a profound difference in CTCF-requirement for genome folding in flies and vertebrates, in which a large fraction of boundaries are CTCF-dependent and suggest that CTCF has played mutable roles in genome architecture and direct gene expression control during metazoan evolution.

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Section: Ctcf Impacts Expression Patterns Of Genes Near Ctcf Peaksmentioning

confidence: 81%

Section: Ctcf Impacts Expression Patterns Of Genes Near Ctcf Peaksmentioning

confidence: 99%

CTCF loss has limited effects on global genome architecture in Drosophila despite critical regulatory functions

et al. 2021

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“…The Mcp boundary contains binding sites for dCTCF and Pita [ 145 ]. The Fub boundary contains binding sites for CTCF, Su(Hw), and Pita [ 145 , 146 , 147 ]. Similar to dCTCF, Su(Hw) and Pita have clusters of C2H2 domains, some of which facilitate the specific binding of these proteins with DNA motifs [ 148 , 149 , 150 ].…”

Section: Super-long-distance Interactions In the Drosophmentioning

confidence: 99%

Mechanisms of Enhancer-Promoter Interactions in Higher Eukaryotes

Kyrchanova

Georgiev

2021

IJMS

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In higher eukaryotes, enhancers determine the activation of developmental gene transcription in specific cell types and stages of embryogenesis. Enhancers transform the signals produced by various transcription factors within a given cell, activating the transcription of the targeted genes. Often, developmental genes can be associated with dozens of enhancers, some of which are located at large distances from the promoters that they regulate. Currently, the mechanisms underlying specific distance interactions between enhancers and promoters remain poorly understood. This review briefly describes the properties of enhancers and discusses the mechanisms of distance interactions and potential proteins involved in this process.

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“…The Zw5 protein was originally identified as a key factor of the scs insulator at the boundary of the hsp70 cluster ( 18 , 19 ) and can effectively support long-range interaction between its binding sites ( 20 ). The Pita protein functions in cooperation with dCTCF and Su(Hw) in organization of insulator/boundary elements in the bithorax complex ( 21 , 22 ). In transgenic lines, the ZAF1 protein can form a chromatin loop that isolates the eye enhancer from the white gene ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

Structural basis of diversity and homodimerization specificity of zinc-finger-associated domains in Drosophila

Bonchuk

Boyko

Fedotova

et al. 2021

Nucleic Acids Research

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In arthropods, zinc finger-associated domains (ZADs) are found at the N-termini of many DNA-binding proteins with tandem arrays of Cys2-His2 zinc fingers (ZAD-C2H2 proteins). ZAD-C2H2 proteins undergo fast evolutionary lineage-specific expansion and functional diversification. Here, we show that all ZADs from Drosophila melanogaster form homodimers, but only certain ZADs with high homology can also heterodimerize. CG2712, for example, is unable to heterodimerize with its paralog, the previously characterized insulator protein Zw5, with which it shares 46% homology. We obtained a crystal structure of CG2712 protein's ZAD domain that, in spite of a low sequence homology, has similar spatial organization with the only known ZAD structure (from Grauzone protein). Steric clashes prevented the formation of heterodimers between Grauzone and CG2712 ZADs. Using detailed structural analysis, site-directed mutagenesis, and molecular dynamics simulations, we demonstrated that rapid evolutionary acquisition of interaction specificity was mediated by the more energy-favorable formation of homodimers in comparison to heterodimers, and that this specificity was achieved by multiple amino acid substitutions resulting in the formation or breaking of stabilizing interactions. We speculate that specific homodimerization of ZAD-C2H2 proteins is important for their architectural role in genome organization.

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The insulator functions of theDrosophilapolydactyl C2H2 zinc finger protein CTCF: Necessity versus sufficiency

Cited by 34 publications

References 41 publications

CTCF loss has limited effects on global genome architecture in Drosophila despite critical regulatory functions

CTCF loss has limited effects on global genome architecture in Drosophila despite critical regulatory functions

Mechanisms of Enhancer-Promoter Interactions in Higher Eukaryotes

Structural basis of diversity and homodimerization specificity of zinc-finger-associated domains in Drosophila

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