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Related Concept Videos

Transcription Factors02:16

Transcription Factors

76.7K
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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General Transcription Factors01:30

General 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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Conserved Binding Sites01:49

Conserved Binding Sites

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Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
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Cooperative Binding of Transcription Regulators02:13

Cooperative Binding of Transcription Regulators

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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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Master Transcription Regulators02:23

Master Transcription Regulators

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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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Eukaryotic Transcription Activators02:42

Eukaryotic Transcription Activators

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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.
The binding domains are capable of recognizing and interacting with regulatory sequences on the DNA. These...
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Related Experiment Video

Updated: Sep 9, 2025

High Sensitivity Measurement of Transcription Factor-DNA Binding Affinities by Competitive Titration Using Fluorescence Microscopy
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High Sensitivity Measurement of Transcription Factor-DNA Binding Affinities by Competitive Titration Using Fluorescence Microscopy

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Predicting the DNA binding specificity of transcription factor mutants using family-level biophysically interpretable

Shaoxun Liu1, Pilar Gomez-Alcala1, Christ Leemans1

  • 1Department of Biological Sciences, Columbia University, New York, NY 10027, United States.

Nucleic Acids Research
|August 28, 2025
PubMed
Summary

We developed a novel method to predict how mutations affect transcription factor (TF) DNA binding. This approach accurately forecasts changes in binding energy for TF mutants, aiding disease mutation impact studies.

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Area of Science:

  • Molecular Biology
  • Genomics
  • Biophysics

Background:

  • Transcription factors (TFs) mediate crucial cellular processes through sequence-specific DNA binding.
  • High-throughput assays and machine learning have advanced the definition of TF-DNA recognition.
  • Understanding mutation effects on TF binding is vital for disease research.

Purpose of the Study:

  • To develop a method for predicting the impact of mutations in TF DNA-binding domains on sequence preference.
  • To accurately quantify shifts in binding free energy (ΔΔΔG/RT) for TF mutants.

Main Methods:

  • Developed a reference-free tetrahedral representation for base preference variation within TF structural families.
  • Utilized high-quality DNA binding models of wild-type TFs.
  • Applied the method to basic helix-loop-helix (bHLH) and homeodomain (HD) TF families.

Main Results:

  • Demonstrated the feasibility of accurately predicting mutation-induced shifts in TF binding free energy.
  • Successfully predicted changes in binding energy for TF mutants using the developed method.
  • Validated the approach on bHLH and HD TF families.

Conclusions:

  • The developed method enables accurate prediction of mutation effects on TF-DNA binding affinity.
  • This approach provides a powerful tool for interpreting disease-associated mutations in TFs.
  • Leveraging existing TF binding data can significantly advance predictive capabilities in molecular recognition.