Sequence properties of human acidic transcriptional activation domains
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ABSTRACT:
PROVIDER: PRJNA786592 | ENA |
REPOSITORIES: ENA
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Project description:Acidic activation domains are intrinsically disordered regions of transcription factors that bind coactivators. The intrinsic disorder and low evolutionary conservation of activation domains have made it difficult to identify the sequence features controlling AD activity. To address this problem, we designed thousands of variants in seven acidic activation domains and measured their activities with a new high-throughput assay in human cell culture. We found that strong activation domain activity required a balance between the number of acidic residues and aromatic and leucine residues. These findings motivated a predictor of activation domains that scans the human proteome for clusters of aromatic and leucine residues embedded in regions of high acidity. This predictor identifies known activation domains and accurately predicts new ones. Our results support a flexible model of activation domains in which acidic residues solubilize hydrophobic motifs so that they can interact with coactivators.
2021-12-08 | GSE190288 | GEO
Project description:Chromatin three-dimensional (3D) organization inside the cell nucleus determines the separation of euchromatin and heterochromatin domains. Their segregation results in the definition of active and inactive chromatin compartments, whereby the local concentration of associated proteins, RNA and DNA results in the formation of distinct subnuclear structures. Thus, chromatin domains spatially confined in a specific 3D nuclear compartment are expected to share similar epigenetic features and biochemical properties, in terms of accessibility and solubility. Based on this rationale, we developed the 4f-SAMMY-seq to map euchromatin and heterochromatin based on their accessibility and solubility, starting from as little as 10,000 cells. Adopting a tailored bioinformatic data analysis approach we reconstruct also their 3D segregation in active and inactive chromatin compartments and sub-compartments, thus recapitulating the characteristic properties of distinct chromatin states. A key novelty of the new method is the capability to map both the linear segmentation of open and closed chromatin domains, as well as their 3D compartmentalization in one single experiment.
2024-05-13 | GSE262102 | GEO
Project description:Chromatin three-dimensional (3D) organization inside the cell nucleus determines the separation of euchromatin and heterochromatin domains. Their segregation results in the definition of active and inactive chromatin compartments, whereby the local concentration of associated proteins, RNA and DNA results in the formation of distinct subnuclear structures. Thus, chromatin domains spatially confined in a specific 3D nuclear compartment are expected to share similar epigenetic features and biochemical properties, in terms of accessibility and solubility. Based on this rationale, we developed the 4f-SAMMY-seq to map euchromatin and heterochromatin based on their accessibility and solubility, starting from as little as 10,000 cells. Adopting a tailored bioinformatic data analysis approach we reconstruct also their 3D segregation in active and inactive chromatin compartments and sub-compartments, thus recapitulating the characteristic properties of distinct chromatin states. A key novelty of the new method is the capability to map both the linear segmentation of open and closed chromatin domains, as well as their 3D compartmentalization in one single experiment.
2024-05-13 | GSE262103 | GEO
Project description:Chromatin three-dimensional (3D) organization inside the cell nucleus determines the separation of euchromatin and heterochromatin domains. Their segregation results in the definition of active and inactive chromatin compartments, whereby the local concentration of associated proteins, RNA and DNA results in the formation of distinct subnuclear structures. Thus, chromatin domains spatially confined in a specific 3D nuclear compartment are expected to share similar epigenetic features and biochemical properties, in terms of accessibility and solubility. Based on this rationale, we developed the 4f-SAMMY-seq to map euchromatin and heterochromatin based on their accessibility and solubility, starting from as little as 10,000 cells. Adopting a tailored bioinformatic data analysis approach we reconstruct also their 3D segregation in active and inactive chromatin compartments and sub-compartments, thus recapitulating the characteristic properties of distinct chromatin states. A key novelty of the new method is the capability to map both the linear segmentation of open and closed chromatin domains, as well as their 3D compartmentalization in one single experiment.
2024-05-13 | GSE226718 | GEO
Project description:Transcription factors can promote gene expression through activation domains. Whole-genome screens have systematically mapped activation domains in transcription factors, but not in non-transcription factor proteins (e.g., chromatin regulators, coactivators). To fill this knowledge gap, we employed the activation domain predictor PADDLE to analyze the proteomes of Arabidopsis thaliana and Saccharomyces cerevisiae. We screened 18,000 predicted activation domains from >800 non-transcription factor genes in both species, confirming that 89% of candidate proteins contain active fragments. Our work enables the annotation of hundreds of nuclear proteins as putative coactivators, many of which have never been ascribed any function in plants. Analysis of peptide sequence compositions reveals how the distribution of key amino acids dictates activity. Finally, we validated short, 'universal' activation domains with comparable performance to state-of-the-art activation domains used for genome engineering. Our approach enables the genome-wide discovery and annotation of activation domains that can function across diverse eukaryotes.
2024-04-24 | GSE247147 | GEO
Project description:Mycobacterium avium complex (MAC), including Mycobacterium avium and Mycobacterium intracellulare (MI), accounts for a significant portion of nontuberculous mycobacterial lung disease affecting immunocompromised and lung structural disease patients. Adapting pathogens to a host-induced hostile environment is critical to establishing infection and persistence within the host. However, the cellular and molecular mechanisms of stress response for MAC still need to be elucidated. In this study, we analyzed the transcriptional profile of MI under acidic and oxidative stress conditions using RNA-seq. At the transcriptome level, 80 genes were shown [FC] ≥2.0 and p <0.05 under oxidative stress with 10 mM hydrogen peroxide. In detail, 77 genes were upregulated, while 3 genes were downregulated. Also, 878 genes were shown [FC] ≥2.0 and p <0.05 under acidic stress with pH 4.5. Among these genes, 339 were upregulated, while 539 were downregulated. Functional analysis revealed the activation of several pathways, including nitrogen and sulfur metabolism, under acidic stress conditions. On the contrary, oxidative stress conditions activated DNA replication and repair pathways. Our data demonstrate the activation of nitrogen and sulfur metabolism in MAC infection, which could be crucial for persistence and survival under stress conditions encountered within the host during infection. In conclusion, this study suggests the importance of stress responses in MAC pathogenesis and identifies potential therapeutic target pathways.
2024-02-21 | GSE244264 | GEO
Project description: Not available
| S-EPMC1219057 | biostudies-other
Project description:The purpose of this study was to examine how Mtb integrates acidic pH and available carbon sources as environmental cues to regulate its metabolism and growth rate. RNA-seq transcriptional profiling of M. tuberculosis growing at acidic or neutral pH, in pyruvate or glycerol, was examined. These studies identified carbon source-dependent and -independent pH-dependent adaptations.
2014-07-07 | GSE52020 | GEO
Project description:The purpose of this study was to examine how Mtb integrates acidic pH and available carbon sources as environmental cues to regulate its metabolism and growth rate. RNA-seq transcriptional profiling of M. tuberculosis growing at acidic or neutral pH, in pyruvate or glycerol, was examined. These studies identified carbon source-dependent and -independent pH-dependent adaptations. Mtb strain CDC1551 was grown in standing T-75 flasks in 40 mL of medium seeded an initial OD of 0.1. We examined medium in four conditions pH 7.0 10 mM glycerol, pH 5.7 10 mM glycerol, pH 7.0 10 mM pyruvate, pH 5.7 10 mM pyruvate. Following 3 days of incubation at 37C, RNA was isolated from the bacterial cultures and used for RNA-seq.
2014-07-07 | E-GEOD-52020 | biostudies-arrayexpress
Project description:Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin (IL)-2, a critical cytokine in T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation and anti-tumor immunity by CD8+ T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Ra with higher affinity, triggers STAT5 activation and drives CD8+ T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Finally, we find that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.
2022-12-02 | GSE213440 | GEO