Multiscale Nature of Collinearity in Embryonic HOX Gene Cluster Activation

A fundamental property in embryonic development is the collinearity of Hox gene cluster activation as first observed by E.B. Lewis (Lewis, 1978). This collinearity consists of the sequential ordering of the Hox genes along the telomeric to centromeric direction on the DNA fiber and the sequential activation of these genes in the same order in the ontogenetic units along the anterior to posterior axis of an embryo. The size of a Hox gene cluster on the DNA fiber and a vertebrate embryonic size differ by more than 4 orders of magnitudes. The correlation of these entities so different in their dimensions set up a multiscale phenomenon. Such phenomena characterize the Complex Systems which are studied by different disciplines in coordination like Physics, Mathematics, Chemistry etc. According to the current dogma in Developmental Biology, the Hox gene collinearity phenomenon is treated as an exclusively biomolecular phenomenon.
I have proposed a biophysical model (BM) taking into account the multiscale nature of the Hox gene collinearity (Papageorgiou, 2001). More specifically physical forces were introduced which pull the Hox genes sequentially out of the cluster toward a nuclear domain where gene transcription can occur. The vertebrate Hox gene cluster is represented by an expanding elastic spring (Papageorgiou, 2017). One end of this spring is free to move in the telomeric direction from the Hox cluster while the other end is fastened in the neighboring centromeric domain of the DNA fiber. The predictions of the BM are confirmed. For example, it is predicted that during Hox gene activation the Hox cluster is sequentially elongated. Recent experimental findings verify this elongation prediction (Fabre et al., 2015).
Following the above BM verifications, another application of the BM is proposed in a different research area, namely Cancer. It is observed that several cancers appear when a Hox gene cluster is abnormally elongated. I assume that this abnormal elongation is the cause of cancer and I propose the following hypothesis: the Hox clusters, as expanding elastic springs, are abnormally elongated when the fastening domain of the spring is modified. This can occur after a spontaneous (or experimental) mutation in the neighboring to the cluster centromeric domain. The mutation may change the fastening ability of the spring, altering thus the normal elongation of the Hox gene cluster. This hypothesis can be tested by digging in the Big Data Bases of the DNA sequences of several vertebrates that already exist (Papageorgiou, 2018). The search consists in establishing eventual concurrence of mutations in the centromeric domain next to the Hox gene clusters and abnormal Hox gene cluster elongations.

Authors: 
Spyros Papageorgiou
Room: 
8
Date: 
Tuesday, September 25, 2018 - 12:45 to 13:00

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