The Human Transcription Factors

Samuel Lambert^1,*, Arttu Jolma^2,*, Laura Campitelli^1,*, Pratyush Das³, Yimeng Yin⁴, Mihai Albu², Xiaoting Chen⁵, Jussi Taipale^{3,4,6,^}, Timothy R. Hughes^{1,2,^}, and Matthew T. Weirauch^{5,7,8,^}

1 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
2 Donnelly Centre, University of Toronto, Toronto, ON, Canada
3 Genome-Scale Biology Program, University of Helsinki, Helsinki, Finland
4 Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden
5 Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
6 Department of Biochemistry, Cambridge University, Cambridge, Great Britain
7 Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
8 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

^ To whom correspondence should be addressed:
Matthew.Weirauch@cchmc.org
t.hughes@utoronto.ca
ajt208@cam.ac.uk

Abstract

Transcription factors (TFs) recognize specific DNA sequences to control chromatin and transcription, forming a complex system that guides expression of the genome. Despite keen interest in understanding how TFs control gene expression, it remains challenging to determine how the precise genomic binding sites of TFs are specified and how TF binding ultimately relates to regulation of transcription. This review considers how TFs are identified and functionally characterized, principally through the lens of a catalog of over 1,600 likely human TFs and binding motifs for two-thirds of them. Major classes of human TFs differ markedly in their evolutionary trajectories and expression patterns, underscoring distinct functions. TFs likewise underlie many different aspects of human physiology, disease, and variation, highlighting the importance of continued effort to understand TF-mediated gene regulation.

This website contains the catalog of 1639 known and likely human TFs and their motifs (version 1_01)

We manually examined 2765 proteins compiled by combining putative TF lists from several sources: previous studies (Fulton et al., 2009; Vaquerizas et al., 2009), domain searches (using HMMs and parameters from CisBP (Weirauch et al., 2014) and Interpro (Hunter et al., 2009)), Gene Ontology (Ashburner et al., 2000; Gene Ontology, 2015), and crystal and NMR structures of proteins in complex with DNA (PDB, (Berman et al., 2000)). We then assigned two curators to classify the likelihood of each protein being a TF (TF with a known motif, TF with an inferred motif, likely TF, ssDNA/RNA binding protein, or unlikely TF), and its DNA binding mode (binds as a monomer or homodimer, binds as an obligate heteromer, binds with low specificity, or does not bind DNA). Each curator also took brief notes with citations supporting their assessments. Using data from CisBP and other sources, we recorded whether motifs are known for each TF, along with whether DNA-protein structures are available. We considered global sequence alignments and known DNA binding residues to make decisions for poorly characterized proteins within families where only a subset bind DNA (e.g., ARID, HMG, and Myb (Boyer et al., 2004)). Three senior authors (TRH, MTW, JT) resolved cases of disagreement between reviewers, and reviewed all cases where both curators agreed that a protein without a known DNA-binding domain is likely a bona fide TF. Further details are available in the associated publication (see How to cite page).