Novel Mechanism of Bispecificity in Forkhead Transcription Factors
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ABSTRACT:
PROVIDER: PRJNA448691 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6936920.fastq.gz | Fastqsanger.gz | |||
| SRR6936921.fastq.gz | Fastqsanger.gz | |||
| SRR6936916.fastq.gz | Fastqsanger.gz | |||
| SRR6936917.fastq.gz | Fastqsanger.gz | |||
| SRR6936918.fastq.gz | Fastqsanger.gz |
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Project description:The forkhead transcription factor (TF) FoxN3 recognizes both the canonical forkhead DNA motif (RYAAAYA), as well as a novel alternate motif (GACGC). These two motifs are more distinct than the typically observed primary and secondary motifs of other TFs, as the two motifs cannot be aligned and are not clearly related to each other. Amino acids at the canonical base-contacting positions in the forkhead DNA binding domain are largely conserved throughout the forkhead family, so the ability of FoxN3 and other bispecific forkhead factors to recognize the alternate site cannot be explained by amino acid substitutions at these positions. Neither the mechanism of this bispecific DNA recognition nor its regulatory function are understood. Here we show that human FoxN3 does recognize both motifs in cells. We also report the crystal structures of the FoxN3 DNA binding domain bound to the canonical forkhead binding site, and separately to the alternate DNA binding site. FoxN3 adopts a remarkably similar conformation to recognize both motifs, making contacts with different DNA bases using the same amino acids. However, the DNA structure is significantly altered between the two motifs, allowing the same domain to recognize two motifs of different lengths. Changes between the two structures in the conformation of segments of the forkhead domain outside of the direct DNA-contacting positions contribute to the ability to bind the alternate site. Swapping these segments of the domain between different forkhead proteins changes the ability of proteins to recognize the alternate site, highlighting the importance of non-base-contacting positions in determining TF-DNA binding specificity. The structures present a new mechanism by which a single DBD can recognize two divergent sequences.
2019-02-27 | GSE112672 | GEO
Project description:The replication of eukaryotic chromosomes is organized temporally and spatially within the nucleus through epigenetic regulation of replication origin function. The characteristic initiation timing of specific origins is thought to reflect their chromatin environment or sub-nuclear positioning, however the mechanism remains obscure. Here we show that the yeast Forkhead transcription factors, Fkh1 and Fkh2, are global determinants of replication origin timing. Forkhead regulation of origin timing is independent of local levels or changes of transcription. Instead, we show that Fkh1 and Fkh2 are required for the clustering of early origins and their association with the key initiation factor Cdc45 in G1-phase, suggesting that Fkh1 and Fkh2 selectively recruit origins to emergent replication factories. Fkh1 and Fkh2 bind Fkh-activated origins, and interact physically with ORC, providing a plausible mechanism to cluster origins. These findings add a new dimension to our understanding of the epigenetic basis for differential origin regulation and its connection to chromosomal domain organization.
2012-01-20 | GSE33702 | GEO
Project description:The replication of eukaryotic chromosomes is organized temporally and spatially within the nucleus through epigenetic regulation of replication origin function. The characteristic initiation timing of specific origins is thought to reflect their chromatin environment or sub-nuclear positioning, however the mechanism remains obscure. Here we show that the yeast Forkhead transcription factors, Fkh1 and Fkh2, are global determinants of replication origin timing. Forkhead regulation of origin timing is independent of local levels or changes of transcription. Instead, we show that Fkh1 and Fkh2 are required for the clustering of early origins and their association with the key initiation factor Cdc45 in G1-phase, suggesting that Fkh1 and Fkh2 selectively recruit origins to emergent replication factories. Fkh1 and Fkh2 bind Fkh-activated origins, and interact physically with ORC, providing a plausible mechanism to cluster origins. These findings add a new dimension to our understanding of the epigenetic basis for differential origin regulation and its connection to chromosomal domain organization.
2012-01-20 | GSE33677 | GEO
Project description:Mitotic genes are one of the most strongly oscillating groups of genes in the eukaryotic cell cycle. Understanding the regulation of mitotic gene expression is a key issue in cell cycle control but is poorly understood in most organisms. Here, we find a new mitotic transcription factor, Sak1, in the fission yeast S. pombe. Sak1 belongs to the RFX family of transcription factors, which have not previously been connected to cell cycle control. Sak1 binds upstream of mitotic genes in close proximity to Fkh2, a forkhead transcription factor previously implicated in regulation of mitotic genes. We show that Sak1 is the major activator of mitotic gene expression and also confirm the role of Fkh2 as the opposing repressor. Sep1, another forkhead transcription factor, is an activator for a small subset of mitotic genes involved in septation. From yeasts to humans, forkhead transcription factors are involved in mitotic gene expression, and it will be interesting to see whether RFX transcription factors may also be involved in other organisms.
2014-08-25 | GSE60718 | GEO
Project description:Mitotic genes are one of the most strongly oscillating groups of genes in the eukaryotic cell cycle. Understanding the regulation of mitotic gene expression is a key issue in cell cycle control but is poorly understood in most organisms. Here, we find a new mitotic transcription factor, Sak1, in the fission yeast S. pombe. Sak1 belongs to the RFX family of transcription factors, which have not previously been connected to cell cycle control. Sak1 binds upstream of mitotic genes in close proximity to Fkh2, a forkhead transcription factor previously implicated in regulation of mitotic genes. We show that Sak1 is the major activator of mitotic gene expression and also confirm the role of Fkh2 as the opposing repressor. Sep1, another forkhead transcription factor, is an activator for a small subset of mitotic genes involved in septation. From yeasts to humans, forkhead transcription factors are involved in mitotic gene expression, and it will be interesting to see whether RFX transcription factors may also be involved in other organisms.
2014-08-25 | GSE60712 | GEO
Project description:MHOR002 expression: Forkhead box O transcription factors both suppress and support breast cancer progression.
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Project description:The replication of eukaryotic chromosomes is organized temporally and spatially within the nucleus through epigenetic regulation of replication origin function. The characteristic initiation timing of specific origins is thought to reflect their chromatin environment or sub-nuclear positioning, however the mechanism remains obscure. Here we show that the yeast Forkhead transcription factors, Fkh1 and Fkh2, are global determinants of replication origin timing. Forkhead regulation of origin timing is independent of local levels or changes of transcription. Instead, we show that Fkh1 and Fkh2 are required for the clustering of early origins and their association with the key initiation factor Cdc45 in G1-phase, suggesting that Fkh1 and Fkh2 selectively recruit origins to emergent replication factories. Fkh1 and Fkh2 bind Fkh-activated origins, and interact physically with ORC, providing a plausible mechanism to cluster origins. These findings add a new dimension to our understanding of the epigenetic basis for differential origin regulation and its connection to chromosomal domain organization. These files contain BrdU-IP-seq files (2 replicates for each strain; 5 strains total where WT was used as control). These files also contain RNA-seq data from Asynchronous and G1 arrested WT and Mutant cells (2 replicates per strain and condition; paired end). These files also contain RNA-pol-chip-seq data from Asynchronous and G1 arrested WT and Mutant cells (2 replicates per strain/condition).
2012-01-20 | E-GEOD-33677 | biostudies-arrayexpress
Project description:Many genes are transcriptionally regulated as a function of the cell cycle; genes needed for mitosis are strongly cell cycle regulated. From yeasts to humans, forkhead transcription factors are involved in mitotic gene expression. However, the mechanisms of regulation are unclear, especially since forkhead transcription factors can be activators or repressors, and often function in concert with other proteins. Here, we study mitotic regulation in the fission yeast S. pombe. We find that the forkhead transcription factor Fkh2 is a repressor of many mitotic genes, while a different forkhead transcription factor, Sep1, is an activator of a subset of these genes. The activator of the majority of mitotic genes appears to be Sak1, a transcription factor of the RFX family, which has not previously been implicated in cell cycle control. 3 test samples were analyzed; 1 control (no-tag) sample was processed (each sample has 2 replicate experiments)
2014-08-25 | E-GEOD-60712 | biostudies-arrayexpress
Project description:Many genes are transcriptionally regulated as a function of the cell cycle; genes needed for mitosis are strongly cell cycle regulated. From yeasts to humans, forkhead transcription factors are involved in mitotic gene expression. However, the mechanisms of regulation are unclear, especially since forkhead transcription factors can be activators or repressors, and often function in concert with other proteins. Here, we study mitotic regulation in the fission yeast S. pombe. We find that the forkhead transcription factor Fkh2 is a repressor of many mitotic genes, while a different forkhead transcription factor, Sep1, is an activator of a subset of these genes. The activator of the majority of mitotic genes appears to be Sak1, a transcription factor of the RFX family, which has not previously been implicated in cell cycle control. 24 samples were analyzed. Control for all experiments was the same. The samples are representative of selective spore germination in S. pombe (time course arrays for the WT as well as the mentioned mutants) or the sak1-891 ts strain restrictive temperature time course (WT and ts strain)
2014-08-25 | E-GEOD-60718 | biostudies-arrayexpress
Project description:Forkhead transcription factors bind a canonical consensus DNA motif, RYAAAYA (R = A/G, Y = C/T), as a monomer. However, the molecular mechanisms by which forkhead transcription factors bind DNA as a dimer are not well understood. In this study, we show that FOXO1 recognizes a palindromic DNA element DIV2, and mediates transcriptional regulation. The crystal structure of FOXO1/DIV2 reveals that the FOXO1 DNA binding domain (DBD) binds the DIV2 site as a homodimer. The wing1 region of FOXO1 mediates the dimerization, which enhances FOXO1 DNA binding affinity and complex stability. Further biochemical assays show that FOXO3, FOXM1 and FOXI1 also bind the DIV2 site as homodimer, while FOXC2 can only bind this site as a monomer. Our structural, biochemical and bioinformatics analyses not only provide a novel mechanism by which FOXO1 binds DNA as a homodimer, but also shed light on the target selection of forkhead transcription factors.
| S-EPMC8034652 | biostudies-literature