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Related Concept Videos

Transcription Factors02:16

Transcription Factors

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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
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Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome.  Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form...
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Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
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Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
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Transcription activators are proteins that promote the transcription of genes from DNA to RNA. In most cases, these proteins contain two separate domains ‒ a domain that binds to DNA and a domain for activating transcription; however, in some cases, a single domain is responsible for both binding and activation of transcription, as seen in the glucocorticoid receptor and MyoD.
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Updated: Jun 13, 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 Kisor1, Diego Garrido Ruiz2, Matthew P Jacobson2

  • 1Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA 94143, United States.

Nucleic Acids Research
|June 4, 2025
PubMed
Summary
This summary is machine-generated.

Intracellular pH directly influences gene expression by regulating transcription factor DNA binding. A conserved histidine in transcription factors acts as a pH sensor, altering DNA-binding activity.

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Intracellular pH (pHi) dynamics regulate critical cellular processes like proliferation and differentiation.
  • The role of pHi in directly controlling gene expression via transcription factor activity remains under-explored.
  • Histidine residues in pH-sensing proteins are key mediators of pHi-dependent cellular functions.

Purpose of the Study:

  • To investigate whether transcription factors can act as pH sensors, directly regulating gene expression.
  • To test the hypothesis that histidine residues in transcription factor DNA-binding domains (DBDs) mediate pH-regulated DNA binding.
  • To explore the impact of pHi dynamics on transcription factor binding specificity and cellular behavior.

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 confirm pH-regulated binding affinities.
  • Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) to analyze genome-wide binding and gene expression changes.
  • Site-directed mutagenesis to assess the role of specific histidine residues.

Main Results:

  • Identified pH-dependent DNA-binding motif preferences for FOX family transcription factors (e.g., FOXC2, FOXM1, FOXN1).
  • Demonstrated that binding affinities for FOXC2, FOXM1, and FOXN1 to specific motifs are significantly altered by changes in pHi (pH 7.0 vs. 7.5).
  • Showed that the pH-dependent activity of FOXC2 is mediated by a conserved histidine (His122) in its DBD.
  • ChIP-seq and RNA-seq revealed pH-dependent differences in FOXC2 promoter enrichment and gene expression.

Conclusions:

  • Transcription factors with histidine residues in their DBDs can function as direct pH sensors, exhibiting pH-regulated DNA-binding selectivity.
  • pHi dynamics can directly modulate transcription factor activity, influencing gene expression and cellular behaviors.
  • This mechanism is relevant to over 85 transcription factors across multiple families, highlighting a fundamental regulatory pathway in cell biology.