Transcription Factors and Trans-Acting Regulation

Transcription factors are proteins that bind specific DNA sequences and control the rate of transcription, acting in trans because they are diffusible products that can regulate any target gene carrying their binding site. They are the principal decision-makers of gene expression, integrating cellular signals into the activation or repression of gene programmes.

Definition

Transcription factors are proteins that bind to specific DNA sequences and thereby control the transfer (transcription) of genetic information from DNA to RNA, acting as trans-acting regulators that activate or repress their target genes.

Scope

The topic covers sequence-specific DNA-binding transcription factors, their DNA-binding and activation/repression domains, how they are organised into structural families, and how they recruit or block the basal machinery and cofactors. It distinguishes these trans-acting proteins from the cis-acting DNA elements they read, and from the general factors of the basal machinery. The treatment is reference-educational.

Core questions

• How do transcription factors recognise their specific DNA target sequences?
• How does a bound factor increase or decrease transcription of its target gene?
• How are transcription factors organised into families, and how many does a genome encode?

Key concepts

• Sequence-specific DNA-binding domain
• Activation and repression domains
• DNA-binding structural families (e.g. zinc finger, homeodomain, basic helix-loop-helix, leucine zipper)
• Activators and repressors
• Coactivators and corepressors
• Combinatorial control
• ChIP-seq mapping of binding sites

Key theories

Operon model and regulatory proteins

Jacob and Monod proposed that diffusible regulatory proteins act on specific operator sequences to switch gene transcription on or off, introducing the concept of trans-acting regulation that underlies transcription-factor biology.

Mechanisms

A transcription factor uses a DNA-binding domain to recognise a short specific sequence and a separate effector domain to act on transcription. Activators recruit coactivators and the basal machinery and can help open chromatin, whereas repressors block recruitment, recruit corepressors or compact chromatin. Because many factors bind overlapping sites and act together, gene expression is set combinatorially by the particular set of factors present. Genome-wide binding maps obtained by chromatin immunoprecipitation sequencing have catalogued where factors bind, and curation of DNA-binding proteins has defined the human complement of transcription factors and their families.

Clinical relevance

Transcription factors are central to development and homeostasis, and their misregulation or mutation contributes to cancers and developmental disorders; they are an extensively studied, though historically difficult, class of drug targets. This entry describes their biology at a reference level and is not a basis for individual treatment decisions.

History

The idea of diffusible regulatory proteins acting on specific DNA sites arose from the 1961 operon model. Later structural work defined the major DNA-binding families, and in the genomic era systematic censuses (Vaquerizas et al., 2009; Lambert et al., 2018) catalogued the human transcription-factor repertoire while ChIP-based methods mapped their binding genome-wide.

Key figures

• François Jacob
• Jacques Monod
• Sarah A. Teichmann
• Timothy R. Hughes
• Richard A. Young

Seminal works

• jacob-monod-1961
• lambert-2018
• vaquerizas-2009

Frequently asked questions

Why are transcription factors called trans-acting?

They are diffusible proteins encoded elsewhere in the genome that can act on any target gene carrying their binding sequence, in contrast to cis-acting DNA elements, which only regulate genes on the same molecule.

How do transcription factors find their specific sites in a large genome?

Each factor has a DNA-binding domain that recognises a short sequence motif, and specificity is sharpened by combinatorial binding with partner factors and by the accessibility of the DNA in chromatin.