Abstract
Basic Helix-loop-Helix (bHLH) factors play a significant role in both development and disease. bHLH factors function as protein dimers where two bHLH factors compose an active transcriptional complex. In various species, the bHLH factor Twist has been shown to play critical roles in diverse developmental systems such as mesoderm formation, neurogenesis, myogenesis, and neural crest cell migration and differentiation. Pathologically, Twist1 is a master regulator of epithelial-to-mesenchymal transition (EMT) and is causative of the autosomal-dominant human disease Saethre Chotzen Syndrome (SCS). Given the wide spectrum of Twist1 expression in the developing embryo and the diverse roles it plays within these forming tissues, the question of how Twist1 fills some of these specific roles has been largely unanswered. Recent work has shown that Twist’s biological function can be regulated by its partner choice within a given cell. Our work has identified a phosphoregulatory circuit where phosphorylation of key residues within the bHLH domain alters partner affinities for Twist1; and more recently, we show that the DNA binding affinity of the complexes that do form is affected in a cis-element dependent manner. Such perturbations are complex as they not only affect direct transcriptional programs of Twist1, but they indirectly affect the transcriptional outcomes of any bHLH factor that can dimerize with Twist1. Thus, the resulting lineage-restricted cell fate defects are a combination of loss-of-function and gain-of-function events. Relating the observed phenotypes of defective Twist function with this complex regulatory mechanism will add insight into our understanding of the critical functions of this complex transcription factor.
Highlights
Basic Helix-loop-Helix factors play a significant role in both development and disease. bHLH factors function as protein dimers where two bHLH factors compose an active transcriptional complex
The result of dimerization is the juxtaposition of the basic domains creating a combined DNA binding motif that in the majority of proteins allows for binding to a canonical sequence termed an E-box (CANNTG) [1]
Through the study of the Class B myogenic bHLH factors, it was established that these proteins could drive skeletal muscle specification and differentiation via heterodimer formation with bHLH factors from Class A [2,3,4]
Summary
The bHLH domain is an evolutionarily conserved motif that is well represented from humans to flatworms. The result of dimerization is the juxtaposition of the basic domains creating a combined DNA binding motif that in the majority of proteins allows for binding to a canonical sequence termed an E-box (CANNTG) [1]. HLH proteins can be classified into 5-subclasses, it is convenient to generalize categorization into 3 major classes: ubiquitously expressed bHLH factors (E-proteins Class A); tissue specific/restricted bHLH factors (Class B); and the negative regulatory HLH Id factors, which lack a basic DNA binding domain thereby sequestering E-proteins from forming functional transcriptional complexes [1]. Id class HLH factors could compete for Eproteins as dimer partners adding a critical regulatory input to the system. As additional class B proteins were discovered, this regulatory model was initially applied; it became clear that not all Class B bHLH factors fit this simple paradigm
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