scholarly journals On the prediction of DNA-binding preferences of C2H2-ZF domains using structural models: application on human CTCF

2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Alberto Meseguer ◽  
Filip Årman ◽  
Oriol Fornes ◽  
Ruben Molina-Fernández ◽  
Jaume Bonet ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Binding Site ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Computational Method ◽  
Chromatin Binding ◽  
Input Structure ◽  
Binding Factor ◽  
Potential Binding

Abstract Cis2-His2 zinc finger (C2H2-ZF) proteins are the largest family of transcription factors in human and higher metazoans. To date, the DNA-binding preferences of many members of this family remain unknown. We have developed a computational method to predict their DNA-binding preferences. We have computed theoretical position weight matrices (PWMs) of proteins composed by C2H2-ZF domains, with the only requirement of an input structure. We have predicted more than two-third of a single zinc-finger domain binding site for about 70% variants of Zif268, a classical member of this family. We have successfully matched between 60 and 90% of the binding-site motif of examples of proteins composed by three C2H2-ZF domains in JASPAR, a standard database of PWMs. The tests are used as a proof of the capacity to scan a DNA fragment and find the potential binding sites of transcription-factors formed by C2H2-ZF domains. As an example, we have tested the approach to predict the DNA-binding preferences of the human chromatin binding factor CTCF. We offer a server to model the structure of a zinc-finger protein and predict its PWM.

scholarly journals On the prediction of DNA-binding preferences of C2H2-ZF domains using structural models: application on human CTCF

2019 ◽  
Author(s):  
Alberto Meseguer ◽  
Filip Årman ◽  
Oriol Fornes ◽  
Ruben Molina ◽  
Jaume Bonet ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Binding Site ◽  
Zinc Finger ◽  
Computational Method ◽  
Input Structure ◽  
Binding Factor ◽  
Potential Binding ◽  
Zinc Finger Domains ◽  
Combine Information

ABSTRACTCis2-His2 zinc finger (C2H2-ZF) proteins are the largest family of transcription factors in human and higher metazoans. However, the DNA-binding preferences of many members of this family remain unknown. We have developed a computational method to predict these DNA-binding preferences. We combine information from crystal structures composed by C2H2-ZF domains and from bacterial one-hybrid experiments to compute scores for protein-DNA binding based on statistical potentials. We apply the scores to compute theoretical position weight matrices (PWMs) of proteins with a DNA-binding domain composed by C2H2-ZF domains, with the only requirement of an input structure (experimentally determined or modelled). We have tested the capacity to predict PWMs of zinc finger domains, successfully predicting 3-2 nucleotides of a trinucleotide binding site for about 70% variants of single zinc-finger domains of Zif268. We have also tested the capacity to predict the PWMs of proteins composed by three C2H2-ZF domains, successfully matching between 60% and 90% of the binding-site motif according to the JASPAR database. The tests are used as a proof of the capacity to scan a DNA fragment and find the potential binding sites of transcription-factors formed by C2H2-ZF domains. As an example, we have tested the approach to predict the DNA-binding preferences of the human chromatin binding factor CTCF.

scholarly journals A New Coactivator Function for Zac1's C2H2 Zinc Finger DNA-Binding Domain in Selectively Controlling PCAF Activity

2008 ◽  
Vol 28 (19) ◽  
pp. 6078-6093 ◽  
Author(s):  
Anke Hoffmann ◽  
Dietmar Spengler
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Zinc Finger ◽  
Transcriptional Control ◽  
Zinc Finger Protein ◽  
Embryonic Stem ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Histone H4 ◽  
Histone H4 Acetylation

ABSTRACT The generally accepted paradigm of transcription by regulated recruitment defines sequence-specific transcription factors and coactivators as separate categories that are distinguished by their abilities to bind DNA autonomously. The C2H2 zinc finger protein Zac1, with an established role in canonical DNA binding, also acts as a coactivator. Commensurate with this function, p73, which is related to p53, is here shown to recruit Zac1, together with the coactivators p300 and PCAF, to the p21Cip1 promoter during the differentiation of embryonic stem cells into neurons. In the absence of autonomous DNA binding, Zac1's zinc fingers stabilize the association of PCAF with p300, suggesting its scaffolding function. Furthermore, Zac1 regulates the affinities of PCAF substrates as well as the catalytic activities of PCAF to induce a selective switch in favor of histone H4 acetylation and thereby the efficient transcription of p21Cip1. These results are consistent with an authentic coactivator function of Zac1's C2H2 zinc finger DNA-binding domain and suggest coactivation by sequence-specific transcription factors as a new facet of transcriptional control.

scholarly journals Analysis of DNA Binding by a Eubacterial Zinc Finger Transcription Factor

2009 ◽  
Vol 191 (14) ◽  
pp. 4513-4521 ◽  
Author(s):  
Victor J. McAlister ◽  
Gail E. Christie
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Binding Site ◽  
Zinc Finger ◽  
Specific Binding ◽  
Dna Interaction ◽  
Late Gene ◽  
Major Groove ◽  
Late Gene Expression ◽  
Zinc Finger Transcription Factor

ABSTRACT The Serratia marcescens NucC protein is structurally and functionally homologous to the P2 Ogr family of eubacterial zinc finger transcription factors required for late gene expression in P2- and P4-related bacteriophages. These activators exhibit site-specific binding to a conserved DNA sequence, TGT-N3-R-N4-Y-N3-aCA, that is located upstream of NucC-dependent S. marcescens promoters and the late promoters of P2-related phages. In this report we describe the interactions of NucC with the P2 FETUD late operon promoter P F . NucC is shown to bind P F as a tetramer and to make 12 symmetrical contacts to the DNA phosphodiester backbone. The backbone contacts are centered on the TGT-N3-R-N4-Y-N3-aCA motif. Major groove base contacts can be seen at most positions within the ∼24-bp binding site. Minor groove contacts map to adjacent positions in the downstream half of the binding site, which corresponds to the area in which the DNA also appears to be bent by NucC binding. NucC binding provides a new example of protein-DNA interaction that is strikingly different from the DNA binding demonstrated for eukaryotic zinc-finger transcription factors.

scholarly journals Isolation of a gene encoding a functional zinc finger protein homologous to erythroid Krüppel-like factor: identification of a new multigene family.

1995 ◽  
Vol 15 (11) ◽  
pp. 5957-5965 ◽  
Author(s):  
K P Anderson ◽  
C B Kern ◽  
S C Crable ◽  
J B Lingrel
Keyword(s):  
Dna Binding ◽  
Binding Site ◽  
Zinc Finger ◽  
Reporter Gene ◽  
Zinc Finger Protein ◽  
Erythroid Cell ◽  
Specific Gene ◽  
Beta Globin ◽  
Gene Encoding ◽  
Hybridization Probe

We have identified and characterized the gene for a novel zinc finger transcription factor which we have termed lung Krüppel-like factor (LKLF). LKLF was isolated through the use of the zinc finger domain of erythroid Krüppel-like factor (ELKF) as a hybridization probe and is closely related to this erythroid cell-specific gene. LKLF is expressed in a limited number of tissues, with the predominant expression seen in the lungs and spleen. The gene is developmentally controlled, with expression noted in the 7-day embryo followed by a down-regulation at 11 days and subsequent reactivation. A high degree of similarity is noted in the zinc finger regions of LKLF and EKLF. Beyond this domain, the sequences diverge significantly, although the putative transactivation domains for both LKLF and EKLF are proline-rich regions. In the DNA-binding domain, the three zinc finger motifs are so closely conserved that the predicted DNA contact sites are identical, suggesting that both proteins may bind to the same core sequence. This was further suggested by transactivation assays in which mouse fibroblasts were transiently transfected with a human beta-globin reporter gene in the absence and presence of an LKLF cDNA construct. Expression of the LKLF gene activates this human beta-globin promoter containing the CACCC sequence previously shown to be a binding site for EKLF. Mutation of this potential binding site results in a significant reduction in the reporter gene expression. LKLF and EKLF can thus be grouped as members of a unique family of transcription factors which have discrete patterns of expression in different tissues and which appear to recognize the same DNA-binding site.

CTCF function is modulated by neighboring DNA binding factors

2011 ◽  
Vol 89 (5) ◽  
pp. 459-468 ◽  
Author(s):  
Oliver Weth ◽  
Rainer Renkawitz
Keyword(s):  
Dna Binding ◽  
Binding Site ◽  
Zinc Finger ◽  
Binding Sites ◽  
Zinc Finger Protein ◽  
Gene Activation ◽  
Ctcf Binding ◽  
Paternal Allele ◽  
Ctcf Binding Site ◽  
Enhancer Blocking

The zinc-finger protein CTCF was originally identified in the context of gene silencing and gene repression (Baniahmad et al. 1990; Lobanenkov et al. 1990). CTCF was later shown to be involved in several transcriptional mechanisms such as gene activation (Vostrov et al. 2002) and enhancer blocking (Filippova et al. 2001; Hark et al. 2000; Kanduri et al. 2000; Lutz et al. 2003; Szabó et al. 2000; Tanimoto et al. 2003; Phillips and Corces 2009; Bell et al. 1999; Zlatanova and Caiafa 2009a, 2009b). Insulators block the action of enhancers when positioned between enhancer and promoter. CTCF was found to be required in almost all cases of enhancer blocking tested in vertebrates. This CTCF-mediated enhancer blocking is in many instances conferred by constitutive CTCF action. For some examples however, a modulation of the enhancer blocking activity was documented (Lutz et al. 2003; Weth et al. 2010). One mechanism is achieved by regulation of binding to DNA. It was shown that CTCF is not able to bind to those binding-sites containing methylated CpG sequences. At the imprinting control region (ICR) of the Igf2/H19 locus the binding-site for CTCF on the paternal allele is methylated. This prevents DNA-binding of CTCF, resulting in the loss of enhancer blocking (Bell and Felsenfeld 2000; Chao et al. 2002; Filippova et al. 2001; Hark et al. 2000; Kanduri et al. 2000, 2002; Szabó et al. 2000; Takai et al. 2001). Not only can DNA methylation interfere with CTCF binding to DNA, it was also shown in one report that RNA transcription through the CTCF binding site results in CTCF eviction (Lefevre et al. 2008). In contrast to these cases most of the DNA sites are not differentially bound by CTCF. Even CTCF interaction with its cofactor cohesin does not seem to differ in different cell types (Schmidt et al. 2010). These results indicate that regulation of CTCF activity might be achieved by neighboring factors bound to DNA. In fact, whole genome analyses of CTCF binding sites identified several classes of neighboring sequences (Dickson et al. 2010; Boyle et al. 2010; Essien et al. 2009). Therefore, in this review we will summarize those results for which a combined action of CTCF with factors bound adjacently was found. These neighboring factors include the RNA polymerases I, II and III, another zinc finger factor VEZF1 and the factors YY1, SMAD, TR and Oct4. Each of these seems to influence, modulate or determine the function of CTCF. Thereby, at least some of the pleiotropic effects of CTCF can be explained.

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