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Related Experiment Video

Updated: Jun 24, 2025

High Sensitivity Measurement of Transcription Factor-DNA Binding Affinities by Competitive Titration Using Fluorescence Microscopy
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A role for pH dynamics regulating transcription factor DNA binding selectivity.

Kyle P Kisor, Diego Garrido Ruiz, Matthew P Jacobson

    Biorxiv : the Preprint Server for Biology
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    PubMed
    Summary
    This summary is machine-generated.

    Intracellular pH dynamics directly regulates gene expression by altering transcription factor DNA binding. A conserved histidine in transcription factors acts as a pH sensor, influencing cell behavior.

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    Area of Science:

    • Molecular Biology
    • Cell Biology
    • Biochemistry

    Background:

    • Intracellular pH (pHi) regulates critical cell functions like proliferation and differentiation.
    • The role of pHi in directly controlling gene expression via transcription factors remains largely unexplored.
    • Histidine residues in proteins are key for sensing pH changes.

    Purpose of the Study:

    • To investigate if transcription factors with histidine in their DNA binding domains (DBDs) exhibit pH-regulated activity.
    • To determine if pHi dynamics can directly modulate gene expression through transcription factor function.
    • To identify specific transcription factors and DNA motifs affected by pH changes.

    Main Methods:

    • Systematic Evolution of Ligands by Exponential Enrichment followed by sequencing (SELEX-seq) to identify pH-dependent DNA binding motifs.
    • Electrophoretic mobility shift assays (EMSAs) to quantify binding affinities of FOX transcription factors at different pH levels.
    • RNA sequencing (RNA-seq) to analyze global gene expression changes in response to pHi variations.
    • Site-directed mutagenesis to assess the role of a specific histidine residue in pH-dependent DNA binding.

    Main Results:

    • SELEX-seq identified pH-dependent DNA motif preferences for FOX family transcription factors.
    • Binding affinities of FOXC2, FOXM1, and FOXN1 to the FkhP motif were significantly higher at pH 7.0 compared to pH 7.5.
    • FOXC2 demonstrated enhanced activity on the FkhP motif at lower intracellular pH in cells, dependent on a conserved histidine (His122).
    • RNA-seq revealed pH-dependent enrichment of promoter motifs associated with FOXC2 activity.

    Conclusions:

    • Transcription factors with histidine in their DBDs can function as pH sensors, directly regulating DNA binding and gene expression.
    • pHi dynamics play a crucial role in modulating transcription factor selectivity and cellular behavior.
    • This pH-regulated transcription factor-DNA binding mechanism is relevant to over 85 transcription factors across various families and impacts diverse cell processes.