Physical Forces May Cause the HoxD Gene Cluster Elongation.

Spyros Papageorgiou

doi:10.3390/biology6030032

Abstract

Hox gene collinearity was discovered be Edward B. Lewis in 1978. It consists of the Hox1, Hox2, Hox3 ordering of the Hox genes in the chromosome from the telomeric to the centromeric side of the chromosome. Surprisingly, the spatial activation of the Hox genes in the ontogenetic units of the embryo follows the same ordering along the anterior-posterior embryonic axis. The chromosome microscale differs from the embryo macroscale by 3 to 4 orders of magnitude. The traditional biomolecular mechanisms are not adequate to comprise phenomena at so divergent spatial domains. A Biophysical Model of physical forces was proposed which can bridge the intermediate space and explain the results of genetic engineering experiments. Recent progress in constructing instruments and achieving high resolution imaging (e.g., 3D DNA FISH, STORM etc.) enable the assessment of the geometric structure of the chromatin during the different phases of Hox gene activation. It is found that the mouse HoxD gene cluster is elongated up to 5–6 times during Hox gene transcription. These unexpected findings agree with the BM predictions. It is now possible to measure several physical quantities inside the nucleus during Hox gene activation. New experiments are proposed to test further this model.

Highlights

The two-phases model” (T-PM) relies on the long-range regulatory elements enhancing expression of Hox expression of the Hoxdistinct genes within the distinct topologically associating domains (TAD)
According to the BM the physical separation of Hox genes and their collinear activation are indispensable and non-separable elements of a single mechanism [33,34]. This mechanism incorporates physical forces acting on the DNA fiber and translocating the Hox genes
The gene translocation is followed by gene transcription [33,34]

Summary

Introduction

Lewis discovered in 1978 that some genes (coined later Hox genes) located in sequence on the chromosome in the cell nucleus are expressed in the same order along the Anterior/Posterior (A/P) axis of the developing embryo [1] This correlation is called spatial Hox gene collinearity and since it is intensively studied. The structure of the different clusters varies from species to species and the vertebrates possess well organized and compacted clusters [3] It is the vertebrates, and in particular mice and chicks, that are extensively studied and several models are proposed to explain the accumulated experimental findings of Hox gene transcription. The T-PM relies on the long-range regulatory elements enhancing expression of Hox expression of the Hoxdistinct genes within the distinct topologically associating domains (TAD).

The Biophysical Model

Morphogen Gradient Experiments

New Methods and the Biophysical Model

Some Predictions of the Biophysical Model

Conclusions