Noncanonical binding of transcription factors: time to revisit specificity?

Transcription factors (TFs) are one of the most studied classes of DNA-binding proteins that have a direct functional impact on gene transcription and thus, on human physiology and disease. The mechanisms that TFs use for recognizing target DNA binding sites have been studied for nearly five decades, yet they remain poorly understood. It is classically assumed that a TF recognizes a specific sequence pattern, or motif, as its binding sites. However, recent studies are consistently finding examples of noncanonical binding, that is, TFs binding at sites that do not resemble their sequence motifs. Here we review the current literature on four major types of noncanonical TF binding, namely binding based on DNA shape readout, at Guanine-quadruplex structures, at repeat sequences, and bispecific binding. These examples point to a critical need for studies to unify our current observations, many of which are at odds with the "one TF, one motif" view, into a more comprehensive definition of the DNA-binding specificity of TFs.

[1]  M. Bansal,et al.  Flexibility of flanking DNA is a key determinant of transcription factor affinity for the core motif. , 2022, Biophysical journal.

[2]  M. Hemberg,et al.  High-throughput techniques enable advances in the roles of DNA and RNA secondary structures in transcriptional and post-transcriptional gene regulation , 2022, Genome biology.

[3]  Oren Ram,et al.  Repetitive DNA symmetry elements negatively regulate gene expression in embryonic stem cells. , 2022, Biophysical journal.

[4]  Evan J. Olson,et al.  Systematic analysis of low-affinity transcription factor binding site clusters in vitro and in vivo establishes their functional relevance , 2021, Nature Communications.

[5]  Yinsheng Wang,et al.  A Quantitative Proteomic Approach for the Identification of DNA Guanine Quadruplex-Binding Proteins. , 2021, Journal of proteome research.

[6]  Md. Abul Hassan Samee,et al.  Systematic identification of non-canonical transcription factor motifs , 2021, BMC Molecular and Cell Biology.

[7]  A. Dunker,et al.  On the roles of intrinsically disordered proteins and regions in cell communication and signaling , 2021, Cell Communication and Signaling.

[8]  S. Balasubramanian,et al.  Chemical profiling of DNA G-quadruplex-interacting proteins in live cells , 2021, Nature Chemistry.

[9]  S. Balasubramanian,et al.  Promoter G-quadruplex folding precedes transcription and is controlled by chromatin , 2021, Genome biology.

[10]  S. Balasubramanian,et al.  G-quadruplexes are transcription factor binding hubs in human chromatin , 2021, Genome biology.

[11]  A. Upadhyaya,et al.  An intrinsically disordered region-mediated confinement state contributes to the dynamics and function of transcription factors. , 2021, Molecular cell.

[12]  R. Gordân,et al.  DNA mismatches reveal conformational penalties in protein-DNA recognition , 2020, Nature.

[13]  Julia Zeitlinger,et al.  Seven myths of how transcription factors read the cis-regulatory code. , 2020, Current opinion in systems biology.

[14]  R. Rohs,et al.  Landscape of DNA binding signatures of myocyte enhancer factor-2B reveals a unique interplay of base and shape readout , 2020, Nucleic acids research.

[15]  D. Suter Transcription Factors and DNA Play Hide and Seek. , 2020, Trends in cell biology.

[16]  R. Mann,et al.  Towards a mechanistic understanding of DNA methylation readout by transcription factors. , 2020, Journal of molecular biology.

[17]  Oren Ram,et al.  Transcription Factor Binding in Embryonic Stem Cells Is Constrained by DNA Sequence Repeat Symmetry. , 2020, Biophysical journal.

[18]  M. Bulyk,et al.  Bispecific Forkhead Transcription Factor FoxN3 Recognizes Two Distinct Motifs with Different DNA Shapes. , 2019, Molecular cell.

[19]  Md. Abul Hassan Samee,et al.  A De Novo Shape Motif Discovery Algorithm Reveals Preferences of Transcription Factors for DNA Shape Beyond Sequence Motifs. , 2019, Cell systems.

[20]  T. Przytycka,et al.  Co-SELECT reveals sequence non-specific contribution of DNA shape to transcription factor binding in vitro , 2018, bioRxiv.

[21]  S. Balasubramanian,et al.  Structural basis of G-quadruplex unfolding by the DEAH/RHA helicase DHX36 , 2018, Nature.

[22]  S. Balasubramanian,et al.  Genome-wide mapping of endogenous G-quadruplex DNA structures by chromatin immunoprecipitation and high-throughput sequencing , 2018, Nature Protocols.

[23]  R. Shamir,et al.  Transcription factor family‐specific DNA shape readout revealed by quantitative specificity models , 2017, Molecular systems biology.

[24]  B. Deplancke,et al.  The Genetics of Transcription Factor DNA Binding Variation , 2016, Cell.

[25]  Lin Yang,et al.  DNAshapeR: an R/Bioconductor package for DNA shape prediction and feature encoding , 2015, Bioinform..

[26]  Raluca Gordân,et al.  Nonconsensus Protein Binding to Repetitive DNA Sequence Elements Significantly Affects Eukaryotic Genomes , 2015, PLoS Comput. Biol..

[27]  Michael V. Gormally,et al.  FOXM1 binds directly to non-consensus sequences in the human genome , 2015, Genome Biology.

[28]  R. Mann,et al.  Quantitative modeling of transcription factor binding specificities using DNA shape , 2015, Proceedings of the National Academy of Sciences.

[29]  Florian Finkernagel,et al.  Zinc Finger Independent Genome-Wide Binding of Sp2 Potentiates Recruitment of Histone-Fold Protein Nf-y Distinguishing It from Sp1 and Sp3 , 2015, PLoS genetics.

[30]  Raluca Gordân,et al.  Protein−DNA binding in the absence of specific base-pair recognition , 2014, Proceedings of the National Academy of Sciences.

[31]  Matthew Slattery,et al.  Absence of a simple code: how transcription factors read the genome. , 2014, Trends in biochemical sciences.

[32]  Martha L. Bulyk,et al.  DNA-binding specificity changes in the evolution of forkhead transcription factors , 2013, Proceedings of the National Academy of Sciences.

[33]  D. B. Lukatsky,et al.  DNA sequence correlations shape nonspecific transcription factor-DNA binding affinity. , 2011, Biophysical journal.

[34]  T. Hughes,et al.  Jury remains out on simple models of transcription factor specificity , 2011, Nature Biotechnology.

[35]  R. Mann,et al.  Origins of specificity in protein-DNA recognition. , 2010, Annual review of biochemistry.

[36]  Duilio Cascio,et al.  The shape of the DNA minor groove directs binding by the DNA-bending protein Fis. , 2010, Genes & development.

[37]  Daniel E. Newburger,et al.  Diversity and Complexity in DNA Recognition by Transcription Factors , 2009, Science.

[38]  Stephen C. J. Parker,et al.  Local DNA Topography Correlates with Functional Noncoding Regions of the Human Genome , 2009, Science.

[39]  Stephen C. J. Parker,et al.  Detection of DNA structural motifs in functional genomic elements. , 2007, Genome research.

[40]  P. V. von Hippel,et al.  Nonspecific DNA binding of genome-regulating proteins as a biological control mechanism: measurement of DNA-bound Escherichia coli lac repressor in vivo. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[41]  P. V. von Hippel,et al.  Non-specific DNA binding of genome regulating proteins as a biological control mechanism: I. The lac operon: equilibrium aspects. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[42]  B. Lewin Interaction of regulator proteins with recognition sequences of DNA. , 1974, Cell.

[43]  OUP accepted manuscript , 2021, Nucleic Acids Research.