ReviewModulating transcription factor activity: Interfering with protein-protein interaction networks
Introduction
Transcription factors (TFs) are proteins that coordinate gene expression in a spatial and temporal manner in specific cell types. These proteins act as the control panel of the genome, finely tuning transcriptional regulation and directly shaping organism phenotypes by inducing or maintaining cell fate [1]. Over the past four decades, TFs have been grouped mostly according to their homology domains and phylogenetic conservation [2,3]. However, recently a novel classification has emerged based on TF’s ability to modify the chromatin landscape. This alternative ontology is based on three functional features: local chromatin access (pioneer TFs), self-sustained remodelling (settler TFs) and sporadic occupancy/selective gene activation (migrant TFs) [4,5]. Such a classification relies on two key parameters: sequential protein-protein and protein-DNA interactions which are both essential to modulating gene activation or repression. In addition to this functional classification, TFs display other molecular characteristics that deeply influence their activity:
- 1)
TFs are part of distinct regulatory networks that also elicit multiple simultaneous protein-protein interactions (PPIs).
- 2)
TFs interactions are interchangeable, facilitated mostly by their intrinsically disordered structural characteristics.
- 3)
The nature of TFs protein-protein interactions and their affinity for DNA binding motifs defines gene target selectivity and chromatin binding dynamics.
In this review, we explain why knowledge around these individual components are essential for successful pharmacological targeting of TFs. We propose here a molecular strategy designed to disrupt TF activity via simultaneous interference of multiple protein-protein interactions.
Section snippets
Defining TFs interactomes
Transcription factors are embedded into PPI networks which enable them to display a tightly coordinated activity at enhancers or promoters. These interactions involve other TFs, chromatin remodellers and co-factors to modulate a specific transcriptional response at a precise time window depending on specific cell types. Within these PPIs networks, some TFs play a central role by acting as communication hubs in combination with direct and indirect recruitment of protein partners that establish
Redundancy mechanisms
One of the major characteristics of TFs is their ability to share functional redundancy. In yeast model systems, it has been shown that TF genetic disruption only affects 3% of their putative target [27]. This phenomenon is due to the fact that closely related members of the same phylogenetic group can act interchangeably in a loss of function scenario, to partially rescue the missing TF. This has been defined as paralogue connectivity in yeast [28]. There are some examples of TF redundancy in
Current status of transcription factors pharmacomodulation
The dogma that pharmacological modulation of TFs is near impossible, is progressively being challenged as illustrated by the rising number of reports on TFs chemical inhibition [[36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48]]. Until now, a major concern of developing a drug targeting a specific TF was the risk of interfering with the expression levels of potentially hundreds of target genes. The recent explosion of knowledge in genomics has presented opportunities
The landscape of TF pharmacomodulation in industry
Pharmacomodulation of TF activity can be achieved by modulating their expression (pre-or post-transcriptionally), changing nuclear translocation dynamics, impeding DNA binding activity or interfering with protein partner recruitment. These different avenues of intervention are attempted mostly on nuclear receptors such as the estrogen or androgen receptors, signal transducers such as STAT3, more recently NOTCH effector RBPJ. Other targets have been tumour suppressors (p53), oncogenes (cMyc,
Conclusion
Many TFs are implicated in the aetiology of human rare diseases, which collectively represent large cohorts of patients. This is a strong indicator that these molecular hubs are viable molecular targets relevant to human health with a huge therapeutic potential that has remained untapped so far. It has been nearly 5 decades since the discovery of the first transcription factor and the idea of drugging this class of protein has been around ever since. What has dramatically changed is the
Acknowledgment
This work was supported by grants from the NHMRC (APP1107643 to MF). MF is supported by a NHMRC Career Developmental Fellowship (APP1111169).
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