Similar Datasets
Project description:Eukaryotic gene regulation relies on the binding of sequence-specific transcription factors (TFs). TFs bind chromatin transiently yet occupy their target sites by forming high-local concentration microenvironments (hubs and condensates) that increase the frequency of binding events. Despite their ubiquity, such microenvironments have been difficult to study in endogenous contexts due to technical limitations. Here, we overcome these limitations and investigate how hubs drive TF occupancy at their targets. Using a DNA binding perturbation to a hub-forming TF, Zelda, in Drosophila embryos, we find that hub properties, including the stability and frequencies of associations to targets, are key determinants of TF occupancy. Our data suggest that hub targeting is driven not just by specific DNA motif recognition, but also by a fine-tuned kinetic balance of interactions between TFs and their co-binding partners.
2024-04-15 | GSE263997 | GEO
Project description:Eukaryotic gene regulation relies on the binding of sequence-specific transcription factors (TFs). TFs bind chromatin transiently yet occupy their target sites by forming high-local concentration microenvironments (hubs and condensates) that increase the frequency of binding events. Despite their ubiquity, such microenvironments have been difficult to study in endogenous contexts due to technical limitations. Here, we overcome these limitations and investigate how hubs drive TF occupancy at their targets. Using a DNA binding perturbation to a hub-forming TF, Zelda, in Drosophila embryos, we find that hub properties, including the stability and frequencies of associations to targets, are key determinants of TF occupancy. Our data suggest that hub targeting is driven not just by specific DNA motif recognition, but also by a fine-tuned kinetic balance of interactions between TFs and their co-binding partners.
2024-04-15 | GSE263718 | GEO
Project description:Eukaryotic gene regulation relies on the binding of sequence-specific transcription factors (TFs). TFs bind chromatin transiently yet occupy their target sites by forming high-local concentration microenvironments (hubs and condensates) that increase the frequency of binding events. Despite their ubiquity, such microenvironments have been difficult to study in endogenous contexts due to technical limitations. Here, we overcome these limitations and investigate how hubs drive TF occupancy at their targets. Using a DNA binding perturbation to a hub-forming TF, Zelda, in Drosophila embryos, we find that hub properties, including the stability and frequencies of associations to targets, are key determinants of TF occupancy. Our data suggest that hub targeting is driven not just by specific DNA motif recognition, but also by a fine-tuned kinetic balance of interactions between TFs and their co-binding partners.
2024-04-15 | GSE263999 | GEO
Project description:A fine kinetic balance of interactions directs transcription factor hubs to genes
| PRJNA1100976 | ENA
Project description:A fine kinetic balance of interactions directs transcription factor hubs to genes [RNA-Seq]
| PRJNA1100525 | ENA
Project description:A fine kinetic balance of interactions directs transcription factor hubs to genes [ATAC-Seq]
| PRJNA1098771 | ENA
Project description:A fine kinetic balance of interactions directs transcription factor hubs to genes [Cut and Run]
| PRJNA1100527 | ENA
Project description:Approximately 10% of genes in the human genome are distributed such that their transcription start sites are located less than 1 kb apart on opposite strands. These divergent gene pairs have a single intergenic segment of DNA, which in some cases appears to share regulatory elements, but it is unclear whether these regions represent functional bidirectional promoters or two overlapping promoters. A recent study showed that divergent promoters are enriched for consensus binding sequences of a small group of transcription factors, including the ubiquitous ets-family transcription factor GA-binding protein (GABP). Here we show that GABP binds to more than 80% of divergent promoters in at least one cell type. Furthermore, we demonstrate that GABP binding is correlated and associated with bidirectional transcriptional activity in a luciferase transfection assay. In addition, we find that the addition of a strict consensus GABP site into a set of promoters that normally function in only one direction significantly increases activity in the opposite direction in 67% of cases. Our findings demonstrate that GABP regulates the majority of divergent promoters and suggest that bidirectional transcriptional activity is mediated through GABP binding and transactivation at both divergent and nondivergent promoters.
| S-EPMC2077898 | biostudies-literature
Project description:BackgroundThe binding of transcription factors (TF) to genomic targets is critical in the regulation of gene expression. Short, double-stranded DNA sequence motifs are routinely implicated in TF recruitment, but many questions remain on how binding site specificity is governed.ResultsHerein, we reveal a previously unappreciated role for DNA secondary structures as key features for TF recruitment. In a systematic, genome-wide study, we discover that endogenous G-quadruplex secondary structures (G4s) are prevalent TF binding sites in human chromatin. Certain TFs bind G4s with affinities comparable to double-stranded DNA targets. We demonstrate that, in a chromatin context, this binding interaction is competed out with a small molecule. Notably, endogenous G4s are prominent binding sites for a large number of TFs, particularly at promoters of highly expressed genes.ConclusionsOur results reveal a novel non-canonical mechanism for TF binding whereby G4s operate as common binding hubs for many different TFs to promote increased transcription.
| S-EPMC8063395 | biostudies-literature
Project description:Understanding molecular kinetics, and particularly protein folding, is a classic grand challenge in molecular biophysics. Network models, such as Markov state models (MSMs), are one potential solution to this problem. MSMs have recently yielded quantitative agreement with experimentally derived structures and folding rates for specific systems, leaving them positioned to potentially provide a deeper understanding of molecular kinetics that can lead to experimentally testable hypotheses. Here we use existing MSMs for the villin headpiece and NTL9, which were constructed from atomistic simulations, to accomplish this goal. In addition, we provide simpler, humanly comprehensible networks that capture the essence of molecular kinetics and reproduce qualitative phenomena like the apparent two-state folding often seen in experiments. Together, these models show that protein dynamics are dominated by stochastic jumps between numerous metastable states and that proteins have heterogeneous unfolded states (many unfolded basins that interconvert more rapidly with the native state than with one another) yet often still appear two-state. Most importantly, we find that protein native states are hubs that can be reached quickly from any other state. However, metastability and a web of nonnative states slow the average folding rate. Experimental tests for these findings and their implications for other fields, like protein design, are also discussed.
| S-EPMC2890711 | biostudies-literature