Speed–Specificity Trade-Offs in the Transcription Factors Search for Their Genomic Binding Sites

Abstract

Transcription factors (TFs) regulate gene expression by binding DNA sequences recognized by their DNA-binding domains (DBDs). DBD-recognized motifs are short and highly abundant in genomes. The ability of TFs to bind a specific subset of motif-containing sites, and to do so rapidly upon activation, is fundamental for gene expression in all eukaryotes. Despite extensive interest, our understanding of the TF-target search process is fragmented; although binding specificity and detection speed are two facets of this same process, trade-offs between them are rarely addressed. In this opinion article, we discuss potential speed-specificity trade-offs in the context of existing models. We further discuss the recently described 'distributed specificity' paradigm, suggesting that intrinsically disordered regions (IDRs) promote specificity while reducing the TF-target search time.

Evolution of binding preferences among whole-genome duplicated transcription factors

“…Further, cooperation and competition act to adjust binding profiles and limit paralog interference but, with few exceptions, are not the major factors guiding divergence. In this context, gradual, and promoter-specific divergence is harder to explain within prevailing models for TF specificity, but may be more consistent with the paradigm of distributed specificity we recently proposed ( 1, 73 ).…”

“…Cells express hundreds of TFs that together transit cells between different expression programs. Despite rapid advances, our understanding of transcriptional networks is still fragmented ( 1 ). For example, different TFs that bind to similar DNA sequences in-vitro ( 2–10 ) localize to different genomic sites in-vivo through mechanisms still poorly understood.…”

The needle and the haystack: single molecule tracking to probe the transcription factor search in eukaryotes

“…Also, how much these observations can be generalized to other TFs is unclear. While most of eukaryotic TFs belongs to just a few classes with rather stereotyped domains involved in specific DNA binding [ 3 ], the protein regions responsible for non-specific interactions with DNA and compact exploration are often unstructured and more variable across different TFs [ 56 , 57 ]. Thus, it is likely that different TFs could be ‘guided’ differently by the nuclear environment, and consequently display different search strategies.…”

“…In this simplified scenario, τ search values would range between minutes in bacteria to days for mammalian TFs (Figure 1A), numbers that appear incompatible with the rapid transcriptional responses observed in living cells [3]. Starting from the 70s, pioneering in vitro studies evidenced that bacterial TFs can find their targets orders of magnitude faster than the Smoluchowski limit, and this discovery stimulated the investigation of an alternative model to describe the TF search, named facilitated diffusion [4,5].…”

“…Transcription Factors (TFs) control the expression of their target genes by recognizing specific sequences in regulatory elements (REs) of chromosomal DNA at the single base-pair level. If we idealize the explored environment as a well-stirred non-crowded solution, the time τ search taken by a TF to reach a target of size a within a volume V via unhindered random three-dimensional (3D) diffusion (with diffusion coefficient D ) is given by the Smoluchowski relationship for diffusion-limited reactions [ 1 , 2 ]: In this simplified scenario, τ search values would range between minutes in bacteria to days for mammalian TFs ( Figure 1A ), numbers that appear incompatible with the rapid transcriptional responses observed in living cells [ 3 ]. Starting from the 70s, pioneering in vitro studies evidenced that bacterial TFs can find their targets orders of magnitude faster than the Smoluchowski limit, and this discovery stimulated the investigation of an alternative model to describe the TF search, named facilitated diffusion [ 4 , 5 ].…”