Biophysics Precedes Biochemistry In Hox Gene Collinearity

Background: Hox gene collinearity is a universal phenomenon most emphatically observed during the development of vertebrate embryos. The last decade or so, a series of genetic engineering experiments have been performed including Hox gene deletions, duplications or transpositions. These experiments are illuminating and helpful to understand the mechanisms responsible for Hox gene collinearity. Until now several models have been proposed based on well established biomolecular mechanisms. Even though these models, and in particular the ‘two-waves model’, efficiently describe many features of the phenomenon, they leave several other findings unexplained. Results: A ‘biophysical model’ has been proposed in a series of publications, based on quite a different hypothesis, namely the generation of physical forces. These forces act on the Hox clusters and translocate the genes step by step from inside the chromatin territory, where they remain inactive, toward the transcription factory domain where they can be transcribed. This model feature was recently confirmed. The corpus of data can be explained by the biophysical model, even in parts where the two-waves model is not successful. Furthermore, the biophysical model can reproduce the wide class of experimental findings after implanting signalling molecules (e.g. FGF or SHH) in the developing vertebrate limb bud. Conclusion: Hox gene transcription proceeds in two steps: firstly, a physical force is generated that moves the genes gradually and in a timely manner to a location where activation is possible. Subsequently, the bio-molecular machinery (e.g. enhancers, repressors etc) takes over and completes the transcription of Hox genes. Experiments are proposed to test this hypothesis.