The following guest post is by Barry Jacobson on his preprint “Dynamic DNA Processing: A Microcode Model of Cell Differentiation”, arXived here.
The paper suggests that DNA should be viewed as a processor that operates by means of base-pairing with remote regions of the genome. If one sequence matches another (or is complementary to it) it will set up a structural loop, or other interaction. However, the paper postulates that at least one region of the genome of every cell will have a unique clock sequence that is shared by no other cell. Therefore, the clock of one cell may not match the same distant sequences as the clock of another. Thus, the pattern of loops that is formed, and the overall 3-D DNA structure, may differ from cell to cell. This will either assist or hinder binding of transcription factors in one type of cell, as compared to another, thus providing a mechanism of differential gene expression.
We discuss a method by how these differing clock sequences could be generated in cell division, so that the daughters each end up with a unique identifier. The identifier then unlocks certain conformations only for those cell types for which it is relevant. Similarly, SNP’s may function in a similar manner, by modifying 3-D configurations, thus altering TF activity.
We further postulate that if a clock or target is errantly mutated, so that it matches a target farther away than was intended, it may stretch the chromosome to the breaking point, and this is the cause of chromosomal breakage or translocations in cancer.
Finally, we allow for the possibility that a cell can modify its clock in response to the environment, such as when healing from trauma, or accepting a graft, in which case it needs to coordinate with neighboring cells. We suggest that perhaps chemical analogs of cell surface proteins may occasionally mistrigger such a clock modification, when none is necessary, and thereby cause incorrect matches and conformations in that cell, which can damage DNA, and lead to cancer, as before.
We realize this is all purely speculative, but we mention that we originally submitted this model to Nature without success 16 years ago, and since then, a number of its assumptions have been verified, as detailed in the recent submission to arXiv, therefore we believe it deserves a second look.