IceQream: Quantitative chromosome accessibility analysis using physical TF models
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE305339 | GEO | 2025/08/24
REPOSITORIES: GEO
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Project description:Transcription factor (TF) dosage is a critical determinant of cellular identity. However, the quantitative relationship between TF dosage and its regulation of chromatin accessibility and gene expression remains poorly understood. To address this, we developed RoboATAC, a scalable, automated ATAC-seq platform for high-throughput accessibility profiling. We then systematically profiled genome-wide chromatin accessibility and gene expression changes induced by graded overexpression of 22 TFs in HEK293T cells (246 total samples), observing dose-dependent changes in accessibility and aggregate TF footprints. Modeling accessibility as a function of sequence and chromatin states revealed that DNA sequence alone accurately predicts dosage sensitivity at elements that become accessible, with low-affinity motifs requiring higher TF levels to induce accessibility. Interpretable deep learning models revealed contributions of motif orientation, spacing, and flanking bases to accessibility, both recapitulating known motifs and nominating novel dosage-sensitive motif arrangements. Nucleosome positioning analysis uncovered two distinct, TF identity dependent patterns by which accessibility is established by changing nucleosome position and occupancy.
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Project description:Isoquinolines (IQs) are natural substances with antibiotic potential. IQ-238 is a synthetic analog of the novel-type N,C-coupled naphtylisoquinoline (NIQ) alkaloid ancisheynine. Gene expression data, cytotoxicity measurements and metabolic modelling is combined to assess the effects of the N,C-coupled naphtylisoquinoline (NIQ) compound IQ-238 on Staphylococcus aureus and man as a potential lead for novel antibiotics. It possesses a high activity against staphylococci but has low cytotoxicity in human cell lines. Genome annotation identified missed enzymes (validated by PCR) in the primary (e.g. nucleotide) metabolism of staphylococci. Gene expression changed after cultivation with IQ-238. Metabolic modelling did yield the adaptations of all central enzymes, including those not affected by significant gene expression changes. The data show that IQ-238 interferes with the carbohydrate metabolism in staphylococci. The data suggest that IQ-238 is a promising lead for antibiotic therapy against S. aureus infections.
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