If eukaryotic chromosomes are composed of complex circular structures instead of the simple linear structures assumed by mainstream science, how are replication, tissue differentiation, and gene expression regulated?
Since this is a blog and not a scientific treatise, let me try to put this into a nutshell:
Cellular differentiation may involve two distinctly different kinds of processes:
1) Binding up of much of the pristine genome into inactive heterochromatin. This process is reversible, allowing for this portion of the genome to be recruited at some later date (partial dedifferentiation).
2) Permanent alteration of most of the remaining origins of replication in a way that either converts them into promoters of transcription, RNA splice sites, or enhancers of transcription.
Permanent alterations of origins may actually involve double origins shared by two adjacent circular DNA elements. During the course of promoter formation, the internal sequences of this double origin may be deleted out, causing a partial fusion of the two circular elements into a large circular element. A similar process could also occur with splice sites, except that additional sequences are removed. Alternatively, these circular elements may completely separate, leaving each circle with a single, simple origin. One circle is deleted from the genome, the other circle remains attached and the single origin becomes an enhancer.
In other words, at one point in time, origins, promoters, splice sites, and, enhancers may have been one and the same. You can learn more about these hypotheses by delving into the blog and looking at the models page tab.
This model also allows for enhancers of transcription to be physically much closer to their promoters even though they may appear much farther away when these circulars are ripped apart by conventional DNA analysis procedures. The larger the circular element, the further away the enhancer appears from its promoter if the circle is split between the promoter and its nearby enhancer.
Undifferentiated replicon cluster
Differentiated replicon cluster
Evolution of the chromosome using this model
Now, we can take this model a step further and consider the evolution of chromosomes over geologic spans of time. In this scenario, there would exist ancient promoters, splice sites, and enhancers that “differentiated” eons ago from ancient origins of replication. These structures would remain “static” during the differentiation process relative to origin modifications. However, they could be excised together with their circular elements during the course of differentiation.
Some heterochromatic compartments may have been locked up eons ago. Failure to do so could result in atavistic characteristics showing up, i.e., partial gene expression of the ancient ancestor.
Cancer “evolves” in the body over time by an incremental increase in DNA rearrangements. Many of these alterations may be destroyed by apoptosis or even necrosis followed by phagocytosis. However, partial clusters of actively replicating DNA circular complexes could easily be incorporated either by the host cell or nearby neighbors. Such dramatic changes in the genome would either kill the cell or corrupt its replication and transcriptional machinery.
Implications of the model on stem cell research
Stem cells would exist as compartments of differentiated and undifferentiated DNA. Generating new tissues from stem cells of a different tissue origin would require two things:
1) The original differentiated compartments becomes locked up as heterochromatin.
2) The undifferentiated compartments required to generate the new tissue type would have to be unlocked from heterochromatin and irreversibly differentiated into the new tissue type. These kinds of “hybrid” cells could theoretically revert back to the old state under the right conditions and that would require the new tissue type to be locked back up as heterochromatin.