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A census of human transcription factors: function, expression and evolution

Key Points

  • Transcription factors (TFs) are key cellular components that control gene expression. Their activity determines how cells function and respond to cellular environments.

  • Despite intense scientific interest in transcriptional regulation, there is currently no reliable repertoire of TFs encoded in the human genome; and research in this field will become severely limited without such information.

  • We present an analysis of 1,391 sequence-specific DNA-binding TFs for the human genome, and their functions, genomic organization and evolutionary conservation. Manual curation of each regulator ensures that the data set is of high quality.

  • Less than 30% of TFs have a known regulatory function. Therefore, by integrating genome-scale data sets we assess several properties that provide initial insights into their functions.

  • We analysed expression profiles across numerous healthy organs and tissues, enabling us to define sets of global and tissue-specific regulators that act as combinatorial partners in a two-tier regulatory system.

  • We compared the genomes of 24 eukaryotic organisms, revealing how distinct types of regulators appeared at crucial points during the evolution of the human lineage.

  • One-fifth of TF-encoding genes reside in high-density clusters, which arose from a series of recent recombination events. This clustering might allow their expression to be coordinately controlled.

  • Although this is a first analysis and much remains to be explored, these observations offer useful starting points for further investigations of the regulatory mechanisms underlying biological processes in humans. Eventually, it may be possible to predict the outcomes resulting from the activity of different TFs.


Transcription factors are key cellular components that control gene expression: their activities determine how cells function and respond to the environment. Currently, there is great interest in research into human transcriptional regulation. However, surprisingly little is known about these regulators themselves. For example, how many transcription factors does the human genome contain? How are they expressed in different tissues? Are they evolutionarily conserved? Here, we present an analysis of 1,391 manually curated sequence-specific DNA-binding transcription factors, their functions, genomic organization and evolutionary conservation. Much remains to be explored, but this study provides a solid foundation for future investigations to elucidate regulatory mechanisms underlying diverse mammalian biological processes.

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Figure 1: Current state of knowledge about transcription factors in the human genome.
Figure 2: Transcription factors classified by DNA-binding domain.
Figure 3: Expression level of transcription factors in 32 human organs and tissues.
Figure 4: Heat map representation of transcription factor expression in 32 human organs and tissues.
Figure 5: Conservation of human transcription factors across 24 eukaryotic genomes.
Figure 6: Locations of transcription factor clusters in the human genome.


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The authors thank J. Herrero and A. Vilella for assistance using Ensembl Compara. J.M.V. thanks the Spanish Ministry of Education and Science, the European Science Foundation Exchange Grant and the Marie Curie Biostar programmes for funding. N.M.L. acknowledges funding from EMBL.

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Corresponding authors

Correspondence to Juan M. Vaquerizas or Nicholas M. Luscombe.

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General transcription factor

One of a group of proteins that are essential for transcription from a eukaryotic promoter. They are involved in the formation of the pre-initiation complex and the recruitment of RNA polymerase.


A protein or small molecule that modulates the activity of an enzyme or of another protein complex.


A small highly conserved basic protein, found in the chromatin of all eukaryotic cells. Histones associate with DNA to form nucleosomes.

Chromatin remodelling protein

A protein that mediates transient changes in chromatin accessibility by modifying the methylation or acetylation status of histones or the methylation status of cytosine residues in DNA.

Gene Ontology

(GO). A widely used classification system of gene functions and other gene attributes that uses a controlled vocabulary.


A database of conserved protein families, domains and motifs that can be used to annotate amino acid sequences. The presence of a protein domain is often indicative of a particular molecular function.


A procedure to identify protein ligands. For DNA-binding proteins, the protein is mixed with a pool of double-stranded oligonucleotides that contain a random core of nucleotides flanked by specific sequences. The protein–DNA complex is recovered, the oligonucleotides amplified by PCR and sequenced to reveal the binding specificity of the protein.


Loci in two species that are derived from a common ancestral locus by a speciation event. This is different from paralogous members of a gene family that are derived from duplication events.


The use of high-throughput sequencing techniques for transcriptomic profiling.

Propensity values

A measure of tissue specificity that normalizes the expression value of a TF across all samples, and the expression of all TFs in a single sample. It is commonly used to measure the distribution of amino acids types in different features of protein structures.

Fisher's exact test

A statistical test of independence between two categorical variables.

Protein-binding array

A high-throughput technique to determine DNA-binding affinities of proteins using microarrays displaying synthetic oligonucleotides.


The combination of chromatin immunoprecipitation (ChIP) experiments with high-throughput sequencing techniques to quantitate protein targeting or chromatin modifications across the entire genome.

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Vaquerizas, J., Kummerfeld, S., Teichmann, S. et al. A census of human transcription factors: function, expression and evolution. Nat Rev Genet 10, 252–263 (2009).

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