FHX, a Novel Fork Head Factor with a Dual DNA Binding Specificity

Pérez-Sánchez, Cristina; Gómez-Ferrerı́a, Marı́a Ana; Fuente, Carmen Arias de la; Granadino, Begoña; Velasco, Gloria; Esteban-Gamboa, Andrés; Rey-Campos, Javier

doi:10.1074/jbc.275.17.12909

Cited by 38 publications

(27 citation statements)

References 46 publications

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“…DME also found the HNF-1 motif to be the most overrepresented in the EPD liver set relative to other vertebrate promoters from EPD, with the top-ranking motif resembling the HNF-1 motif. The motif ranked second resembles the POU2F1-binding motif, and the motif ranked third resembles the binding motif for FOXJ2, which is an expression regulator in liver (26).…”

Section: Resultsmentioning

confidence: 98%

Identifying tissue-selective transcription factor binding sites in vertebrate promoters

Smith

Sumazin

Zhang

2005

Proc. Natl. Acad. Sci. U.S.A.

115

133

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We present a computational method aimed at systematically identifying tissue-selective transcription factor binding sites. Our method focuses on the differences between sets of promoters that are associated with differentially expressed genes, and it is effective at identifying the highly degenerate motifs that characterize vertebrate transcription factor binding sites. Results on simulated data indicate that our method detects motifs with greater accuracy than the leading methods, and its detection of strongly overrepresented motifs is nearly perfect. We present motifs identified by our method as the most overrepresented in promoters of liver-and muscle-selective genes, demonstrating that our method accurately identifies known transcription factor binding sites and previously uncharacterized motifs.bioinformatics ͉ motif discovery D issecting the transcription-regulation networks in higher eukaryotes is an immediate challenge for systems biology. Techniques like microarray analysis and chromatin immunoprecipitation have produced a significant volume of expression and localization data that can be used to investigate this machinery. Transcription factors play a prominent role in transcription regulation; identifying and characterizing their binding sites is central to annotating genomic regulatory regions and understanding gene-regulatory networks.Computational methods that use both sequence and expression data to identify transcription factor binding sites (TFBS) are becoming increasingly accurate (1), but binding-site identification in vertebrates remains a difficult problem. Tissue-selective transcription regulation requires more complex regulatory machinery, contributing to less predictable binding-site location (2) and a greater role for combinatorial control (3). Fortunately, knowledge of gene expression in different tissues can facilitate the detection of tissue-selective regulatory elements through comparative analysis of regulatory sequences.Tools for discovering binding sites associated with specific tissues need to be able to identify highly degenerate motifs that are overrepresented in one set of promoters relative to another. Motif-discovery algorithms, such as CONSENSUS (4), MEME (5), and GIBBS MOTIF SAMPLER (6) represent motifs as positionweight matrices and can express sufficient degeneracy, but none of these algorithms focus on relative overrepresentation between two sets of sequences. DMOTIFS (7) identifies the motifs that best discriminate between two sets of sequences, but an initial, and often prohibitively large, set of candidate motifs must be provided. Other methods that allow the user to give a background set (1, 8) use the background to fit a statistical model, which is then used to determine overrepresentation.We describe a general method for discovering TFBSs by identifying motifs based on a relative overrepresentation between two sets of promoters. Our method, DME (discriminating matrix enumerator), uses an enumerative algorithm to exhaustively and efficiently search a discrete space...

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Section: Resultsmentioning

confidence: 98%

Identifying tissue-selective transcription factor binding sites in vertebrate promoters

Smith

Sumazin

Zhang

2005

Proc. Natl. Acad. Sci. U.S.A.

115

133

View full text Add to dashboard Cite

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“…However, there is increasing evidence that Fox proteins recognize multiple related binding sites. For example, FHX (forkhead homologous X) was able to bind to two different types of sequences (46). The type A binding site contained a core element, (A/G)(T/C)AAA(C/T)A, whereas type B differed significantly from the consensus sequence and could not be determined with confidence.…”

Section: Foxi1 Remains Bound To Chromatin Through All Cell Cycle Stagesmentioning

confidence: 99%

The Forkhead Transcription Factor FoxI1 Remains Bound to Condensed Mitotic Chromosomes and Stably Remodels Chromatin Structure

Yan

Crawford

et al. 2006

Molecular and Cellular Biology

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All forkhead (Fox) proteins contain a highly conserved DNA binding domain whose structure is remarkably similar to the winged-helix structures of histones H1 and H5. Little is known about Fox protein binding in the context of higher-order chromatin structure in living cells. We created a stable cell line expressing FoxI1-green fluorescent protein (GFP) or FoxI1-V5 fusion proteins under control of the reverse tetracycline-controlled transactivator doxycycline inducible system and found that unlike most transcription factors, FoxI1 remains bound to the condensed chromosomes during mitosis. To isolate DNA fragments directly bound by the FoxI1 protein within living cells, we performed chromatin immunoprecipitation assays (ChIPs) with antibodies to either enhanced GFP or the V5 epitope and subcloned the FoxI1-enriched DNA fragments. Sequence analyses indicated that 88% (106/121) of ChIP sequences contain the consensus binding sites for all Fox proteins. Testing ChIP sequences with a quantitative DNase I hypersensitivity assay showed that FoxI1 created stable DNase I sensitivity changes in condensed chromosomes. The majority of ChIP targets and random targets increased in resistance to DNase I in FoxI1-expressing cells, but a small number of targets became more accessible to DNase I. Consistently, the accessibility of micrococcal nuclease to chromatin was generally inhibited. Micrococcal nuclease partial digestion generated a ladder in which all oligonucleosomes were slightly longer than those observed with the controls. On the basis of these findings, we propose that FoxI1 is capable of remodeling chromatin higher-order structure and can stably create site-specific changes in chromatin to either stably create or remove DNase I hypersensitive sites.

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“…Fork head factors have been shown to play important roles both during development and in the adult [7]. Fox genes have been causally linked to multiple cellular processes which are often abnormal in cancer cells [8].…”

Section: Introductionmentioning

confidence: 99%