Absence of a simple code: how transcription factors read the genome

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 39; no. 9; pp. 381 - 399
• Main Authors: Slattery, Matthew, Zhou, Tianyin, Yang, Lin, Dantas Machado, Ana Carolina, Gordân, Raluca, Rohs, Remo
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-09-2014
• Subjects: Animals; Binding Sites; Biophysical Phenomena - genetics; chromatin; cofactor; Computational Biology; cooperativity; DNA - genetics; DNA - metabolism; DNA binding specificity models; Genome - genetics; high-throughput binding assays; Humans; Protein Binding; protein-DNA recognition; Transcription Factors - metabolism; DNA binding specificity models; cooperativity; chromatin; high-throughput binding assays; cofactor; protein-DNA recognition
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2014.07.002

•TFs recognize their genomic target sites by using mechanisms at multiple levels.•Models of DNA sequence and shape can capture the in vitro TF binding specificity.•Cofactors, cooperativity, chromatin, and other factors affect in vivo TF binding.•No simple code combines all the various determinants of TF binding specificity.
Transcription factors (TFs) influence cell fate by interpreting the regulatory DNA within a genome. TFs recognize DNA in a specific manner; the mechanisms underlying this specificity have been identified for many TFs based on 3D structures of protein–DNA complexes. More recently, structural views have been complemented with data from high-throughput in vitro and in vivo explorations of the DNA-binding preferences of many TFs. Together, these approaches have greatly expanded our understanding of TF–DNA interactions. However, the mechanisms by which TFs select in vivo binding sites and alter gene expression remain unclear. Recent work has highlighted the many variables that influence TF–DNA binding, while demonstrating that a biophysical understanding of these many factors will be central to understanding TF function.