Non-coding "regulatory" sequences are the hot new molecular topic. There is lots of talking about the "overlooked" functionality of non-coding DNA previously assumed to be junk. The evidence is impressive. Micro-RNA's, for instance, can inhibit the expression of a gene with important phenotypic effects. 1 pair base substitutions in non-coding intron sequences, can produce important differences in the expression pattern of a gene and the resulting phenotype.
But are these sequences truly "regulatory", or just another way how the molecular machinery of the cell can be intervened? Even if we show how a base pair change can trigger the appearance of a new expression site for a gene, it still remains that the genome of those cells is the same as that of those where the gene is not expressed. Some difference other than that base pair exists between body regions, that results in the expression or not of the gene. As expected from a systemic awareness, a base pair change can be the trigger for a new expression site: but it does not single-handedly determine or "regulate" the outcome. Local differences are also involved.
Micro-RNA's, for instance, require to be transcribed to have their effect, and as such, are themselves subjected to "regulation" by transcription factors, promoter sequences, and such. This brings us to the question of the title: who regulates the regulator? Is this way of thinking logically correct, if it always ends relaying regulation to a previous mechanism? Are we looking for some sort of central kernel? A great "on" switch?
The observation that the different cells of the body share the same DNA content demonstrates that these differences cannot be reduced to DNA composition, but epigenetic factors are perforce involved (Lillie's Paradox). Taking this into account, it is easy to understand how development is, in fact, epigenesis. Sequences are far from being regulatory: they are participants in a greatly epigenetic process of development.
-Alexander Vargas aka Sander, Alipio