Diversification of transcription factor–DNA interactions and the evolution of gene regulatory networks

Abstract

Sequence-specific transcription factors (TFs) bind short DNA sequences in the genome to regulate the expression of target genes. In the last decade, numerous technical advances have enabled the determination of the DNA-binding specificities of many of these factors. Large-scale screens of many TFs enabled the creation of databases of TF DNA-binding specificities, typically represented as position weight matrices (PWMs). Although great progress has been made in determining and predicting binding specificities systematically, there are still many surprises to be found when studying a particular TF's interactions with DNA in detail. Paralogous TFs' binding specificities can differ in subtle ways, in a manner that is not immediately apparent from looking at their PWMs. These differences affect gene regulatory outputs and enable TFs to rewire transcriptional networks over evolutionary time. This review discusses recent observations made in the study of TF-DNA interactions that highlight the importance of continued in-depth analysis of TF-DNA interactions and their inherent complexity. This article is categorized under: Biological Mechanisms > Regulatory Biology.

TetR-family transcription factors in Gram-negative bacteria: conservation, variation and implications for efflux-mediated antimicrobial resistance

“…Homologous transcriptional regulators may evolve differentially in different species allowing the acquisition or loss of targets and therefore the further specialisation of the regulator [52]. This means that it is not only the number, but the function, targets and sequence similarity of TFTRs and other regulators which is likely to vary between bacterial species.…”

High-throughput binding affinity measurements for mutations spanning a transcription factor-DNA interface reveal affinity and specificity determinants

“…These conclusions have been further bolstered by experimental evidence that mutations to DNA-contacting residues or core consensus nucleotides often ablate binding (Maerkl and Quake, 2009;De Masi, et al, 2011), creating large fitness penalties that pose evolutionary barriers. Here, the ability to assess many mutations in parallel and measure even subtle differences in affinity suggests that effects of mutations in trans could be compensated for by concomitant changes in nucleotides flanking cis-regulatory elements to preserve transcriptional responses (Beltran, et al, 2004;Rogers and Bulyk, 2018). In addition, the observation that mutations may stabilize helical conformations to promote DNA binding suggests that these residues could allow formation of permissive binding intermediates (Bloom, et al, 2010;Gong, et al, 2013;Jalal, et al, 2019;McKeown, et al, 2014;Starr, et al, 2017).…”

Serial co-expression analysis of host factors from SARS-CoV viruses highly converges with former high-throughput screenings and proposes key regulators

“…In higher organisms, augmented complexity requires an increase in the number of biological functions. This is mainly achieved by expanding regulatory relationships rather than the number of participating genes [ 1 , 2 ]. The combinatorial or regulatory activity of proteins on structural genes seem to account for the genetic plasticity required for development, organ functional diversity, responses to environmental changes and other emergent properties of multicellularity [ 3 , 4 ].…”