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

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Abstract
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.